<SEC-DOCUMENT>0000874015-23-000136.txt : 20230503
<SEC-HEADER>0000874015-23-000136.hdr.sgml : 20230503
<ACCEPTANCE-DATETIME>20230503162820
ACCESSION NUMBER:		0000874015-23-000136
CONFORMED SUBMISSION TYPE:	10-Q
PUBLIC DOCUMENT COUNT:		64
CONFORMED PERIOD OF REPORT:	20230331
FILED AS OF DATE:		20230503
DATE AS OF CHANGE:		20230503

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-Q
		SEC ACT:		1934 Act
		SEC FILE NUMBER:	000-19125
		FILM NUMBER:		23884470

	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-Q
<SEQUENCE>1
<FILENAME>form10q.htm
<DESCRIPTION>IONIS PHARMACEUTICALS INC 10-Q 3-31-2023
<TEXT>
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        </td>

  </tr>

  <tr>

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

    <td style="width: 2%; vertical-align: bottom;">&#160;</td>

    <td style="width: 49%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(Zip Code)</div>
        </td>

  </tr>


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

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

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

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

  <div><br />
  </div>

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


  <tr>

    <td style="width: 37.58%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Title of each class</div>
        </td>

    <td style="width: 2.08%; vertical-align: bottom;">&#160;</td>

    <td style="width: 19.43%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Trading symbol</div>
        </td>

    <td style="width: 1.94%; vertical-align: bottom;">&#160;</td>

    <td style="width: 38.96%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Name of each exchange on which registered</div>
        </td>

  </tr>

  <tr>

    <td style="width: 37.58%; vertical-align: bottom; border-top: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:nonNumeric name="dei:Security12bTitle" id="Fact_6233123177e14fdc8e8a830267e0aa1d" contextRef="c20230101to20230331">Common Stock, $.001 Par Value</ix:nonNumeric></div>
        </td>

    <td style="width: 2.08%; vertical-align: bottom;">&#160;</td>

    <td style="width: 19.43%; vertical-align: bottom; border-top: #000000 2px solid;">
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        </td>

    <td style="width: 1.94%; vertical-align: bottom;">&#160;</td>

    <td style="width: 38.96%; vertical-align: bottom; border-top: #000000 2px solid;">
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        </td>

  </tr>


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

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


  <tr>

    <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>

  </tr>


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

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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
    Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. <ix:nonNumeric name="dei:EntityCurrentReportingStatus" id="Fact_6554168f10c049b19c5ce88caabff0c8" contextRef="c20230101to20230331">Yes</ix:nonNumeric>&#160;<span style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9746;</span> No <span style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9744;</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted and
    posted 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_de26eba3c70e4debae322c611d96901b" contextRef="c20230101to20230331">Yes</ix:nonNumeric>&#160;<span style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9746;</span> No <span style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9744;</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, 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><br />
  </div>

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


  <tr>

    <td style="width: 50%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:nonNumeric name="dei:EntityFilerCategory" id="Fact_a6f20006e0b04dd0969c4ac01d11f640" contextRef="c20230101to20230331">Large Accelerated Filer</ix:nonNumeric>&#160;<span style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9746;</span></div>
        </td>

    <td style="width: 50%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Accelerated Filer <span style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9744;</span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 50%; vertical-align: top;">&#160;</td>

    <td style="width: 50%; vertical-align: top;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 50%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Non-accelerated Filer <span style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9744;</span></div>
        </td>

    <td style="width: 50%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Smaller Reporting Company <span style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonNumeric name="dei:EntitySmallBusiness" id="Fact_729ce686c4434e2cb76f3e5e4f64e65e" contextRef="c20230101to20230331" format="ixt-sec:boolballotbox">&#x2610;</ix:nonNumeric></span></div>
        </td>

  </tr>

  <tr>

    <td style="width: 50%; vertical-align: top;">&#160;</td>

    <td style="width: 50%; vertical-align: top;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Emerging Growth Company <span style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonNumeric name="dei:EntityEmergingGrowthCompany" id="Fact_2629c4bd40f8462d87783979056f785d" contextRef="c20230101to20230331" format="ixt-sec:boolballotbox">&#x2610;</ix:nonNumeric></span></div>
        </td>

  </tr>


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

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">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 Exchange Act. <span style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9744;</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Indicate by check mark whether the registrant is a shell company (as defined in Rule 12(b)-2 of the Securities Exchange Act of 1934).
    Yes <span style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><ix:nonNumeric name="dei:EntityShellCompany" id="Fact_3d8e787bafe54111abd0de397e6dc20d" contextRef="c20230101to20230331" format="ixt-sec:boolballotbox">&#x2610;</ix:nonNumeric></span> No <span style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#9746;</span></div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">The number of shares of voting common stock outstanding as of April 27, 2023 was <ix:nonFraction name="dei:EntityCommonStockSharesOutstanding" id="Fact_b5cdc672e92a4854aa28d01bb95923a8" contextRef="c20230427" unitRef="U001" decimals="INF" scale="0" format="ixt:num-dot-decimal">143,092,117</ix:nonFraction>.</div>

  <div><br />
  </div>

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    <div class="BRPFPageFooter">
      <div><br />
      </div>

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

    <div class="BRPFPageHeader"></div>

  </div>

  <div><br />
  </div>

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

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

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

  <div><br />
  </div>

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


  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">PART I</div>
        </td>

    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">FINANCIAL INFORMATION</div>
        </td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">ITEM 1:</div>
        </td>

    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Financial Statements:</div>
        </td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 14.85pt; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="#BalanceSheet">Condensed Consolidated Balance Sheets</a><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> as of </span>March 31, 2023<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> (unaudited) and </span>December 31, 2022</div>
        </td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; margin-right: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">3</div>
        </td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 14.85pt; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="#IncomeStatementQ1">Condensed Consolidated Statements of Operations</a><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> for the </span>three months ended<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">&#160;</span>March 31, 2023<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> and </span>2022<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> (unaudited)</span></div>
        </td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; margin-right: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">4</div>
        </td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 14.85pt; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="#ComprehensiveIncomeQ1">Condensed Consolidated Statements of Comprehensive
              Loss</a><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> for the </span>three months ended<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">&#160;</span>March 31, 2023<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> and </span>2022<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> (unaudited)</span></div>
        </td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; margin-right: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">5</div>
        </td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 14.85pt; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="#EquityQ1">Condensed Consolidated Statements of Stockholders&#8217; Equity</a><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> for the </span>three months ended<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">&#160;</span>March 31, 2023<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> and </span>2022<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> (unaudited)</span></div>
        </td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; margin-right: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">6</div>
        </td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 14.85pt; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="#CashFlows">Condensed Consolidated Statements of Cash Flows</a><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> for the </span>three months ended<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">&#160;</span>March 31, 2023<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> and </span>2022<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> (unaudited)</span></div>
        </td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; margin-right: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">7</div>
        </td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 14.85pt; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="#Notes">Notes to Condensed Consolidated Financial Statements
              (unaudited)</a></div>
        </td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; margin-right: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">8</div>
        </td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">ITEM 2:</div>
        </td>

    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="#ITEM2MDAQ1">Management&#8217;s Discussion and Analysis of Financial Condition and Results
              of Operations:</a></div>
        </td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 14.85pt; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="#Overview">Overview</a></div>
        </td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; margin-right: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">20</div>
        </td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 14.85pt; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="#ResultsofOperations">Results of Operations</a></div>
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    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; margin-right: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">22</div>
        </td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 14.85pt; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="#Liquidity">Liquidity and Capital Resources</a></div>
        </td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; margin-right: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">28</div>
        </td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">ITEM 3:</div>
        </td>

    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="#Item3MarketRisk">Quantitative and Qualitative Disclosures about Market Risk</a></div>
        </td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; margin-right: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">30</div>
        </td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">ITEM 4:</div>
        </td>

    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="#Item4Controls">Controls and Procedures</a></div>
        </td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; margin-right: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">30</div>
        </td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">PART II</div>
        </td>

    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="#PARTII">OTHER INFORMATION</a></div>
        </td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; margin-right: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">30</div>
        </td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">ITEM 1:</div>
        </td>

    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="#ITEM1">Legal Proceedings</a></div>
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    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; margin-right: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">30</div>
        </td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">ITEM 1A:</div>
        </td>

    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="#ITEM1A">Risk Factors</a></div>
        </td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; margin-right: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">30</div>
        </td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">ITEM 2:</div>
        </td>

    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="#ITEM2">Unregistered Sales of Equity Securities and Use of Proceeds</a></div>
        </td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; margin-right: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">48</div>
        </td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">ITEM 3:</div>
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    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="#ITEM3">Default upon Senior Securities</a></div>
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    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; margin-right: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">48</div>
        </td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">ITEM 4:</div>
        </td>

    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="#ITEM4">Mine Safety Disclosures</a></div>
        </td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; margin-right: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">48</div>
        </td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">ITEM 5:</div>
        </td>

    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="#ITEM5">Other Information</a></div>
        </td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; margin-right: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">48</div>
        </td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">ITEM 6:</div>
        </td>

    <td style="width: 82.21%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="#ITEM6">Exhibits</a></div>
        </td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; margin-right: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">48</div>
        </td>

  </tr>

  <tr>

    <td style="width: 9.88%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 82.21%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 92.08%; vertical-align: top; background-color: #CCEEFF;" colspan="2">
          <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;" href="#SIGNATURES">SIGNATURES</a></div>
        </td>

    <td style="width: 7.92%; vertical-align: bottom; background-color: #CCEEFF;">
          <div style="text-align: right; margin-right: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">49</div>
        </td>

  </tr>


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

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">&#8220;</span>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 class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
    <div class="BRPFPageFooter">
      <div><br />
      </div>

    </div>

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

    <div class="BRPFPageHeader">
      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"><a id="BalanceSheet"><!--Anchor--></a><!--PROfilePageNumberReset%Num%3%%%-->IONIS PHARMACEUTICALS, INC.</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">CONDENSED CONSOLIDATED BALANCE SHEETS</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">(in thousands, except share data)</div>

  <div><br />
  </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; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 31,</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">2023</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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">
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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;">&#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'; font-size: 10pt; font-weight: bold;">(unaudited)</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>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">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;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Current 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: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Cash and cash equivalents</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="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'; 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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    <td valign="bottom" style="vertical-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>

  </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'; font-size: 10pt;">Contracts receivable</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 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'; 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 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'; 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">
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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%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 36pt; color: #000000; font-family: 'Times New Roman'; 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>

    <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'; 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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:nonFraction name="us-gaap:PropertyPlantAndEquipmentNet" id="Fact_4cf8028d82514177b93946aa1df7c264" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">85,158</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:PropertyPlantAndEquipmentNet" id="Fact_5ad23e93b4e4467b9feec47f0d291fee" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">74,294</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: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Right-of-use 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:OperatingLeaseRightOfUseAsset" id="Fact_179ff6a866a84b438c8efa61e8abcbf5" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">179,148</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:OperatingLeaseRightOfUseAsset" id="Fact_c713ea7701c74914bb86349a6cb99f37" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">181,544</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: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Deposits and other 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherAssetsNoncurrent" id="Fact_d40d8e0c343c4faa8c8a1998eaa5093e" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">78,296</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherAssetsNoncurrent" id="Fact_20e82d483df24cd682d948f6abcde7a0" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">75,344</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%; padding-bottom: 4px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:Assets" id="Fact_e57f61237ed14bad8578d2b47564ba8a" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">2,885,221</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:Assets" id="Fact_bacec939ac84418cbf35df017212761d" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">2,533,876</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: 76%; 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>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">LIABILITIES AND STOCKHOLDERS&#8217; EQUITY</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: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">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">&#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'; 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">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AccountsPayableCurrent" id="Fact_e36e66d0552f404099023f535d194dfe" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">10,499</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AccountsPayableCurrent" id="Fact_0c0b6424e746450abd937b9f839aed88" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">17,921</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'; font-size: 10pt;">Accrued compensation</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:EmployeeRelatedLiabilitiesCurrent" id="Fact_552968f4f2a9496e83f175a2ee89b95c" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">18,160</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 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 valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: 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 valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; 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%;">
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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>

    <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'; font-size: 10pt;">Other current liabilities</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>

  </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'; 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>

    <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: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Long-term deferred contract 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">
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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'; font-size: 10pt;"><span style="text-indent: 0pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_17a2fd610eef4cd7a40de4f517482a78" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_25be9d36b918409db46b807933199820" contextRef="c20221231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">0</ix:nonFraction></ix:nonFraction> percent</span>
            convertible senior notes, 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConvertibleDebtNoncurrent" id="Fact_a398a9b03d9944b0a160b5b317b0ca9e" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">623,025</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConvertibleDebtNoncurrent" id="Fact_6c57d7bc997a408eac5f0d23f91ceea6" contextRef="c20221231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">622,242</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'; font-size: 10pt;"><span style="text-indent: 0pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_65f01bf923dd44568923a6ad8fa6fbdd" contextRef="c20221231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_4a872f1b79fe480980648870d88ebb8f" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal">0.125</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConvertibleDebtNoncurrent" id="Fact_714a80b1e06f495582600aaf17011943" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">545,053</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConvertibleDebtNoncurrent" id="Fact_28e26d3aa3364b35803b96f04b984592" contextRef="c20221231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">544,504</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: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Liability related to sale of future royalties, 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>

    <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: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Long-term 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">
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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'; 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">
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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;">
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        </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: 76%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman'; 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">
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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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:Liabilities" id="Fact_f7cd0990ec2c4e71bcb30f7b03262cba" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,960,989</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'; 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%;">
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            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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:CommonStockValue" id="Fact_2ef68db29f344e1f9b9804fb82fc10d1" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">143</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:CommonStockValue" id="Fact_b57e377e7b024f69a86bf33102ea3c25" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">142</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdditionalPaidInCapitalCommonStock" id="Fact_aebda853ea1647d1b274290dee09ac0f" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">2,089,358</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AdditionalPaidInCapitalCommonStock" id="Fact_aee9cda9e03b48d4a74d89f28e31f6ec" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">2,059,850</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'; 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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AccumulatedOtherComprehensiveIncomeLossNetOfTax" id="Fact_5df551453918447e8a86ae46f488bc1a" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">48,983</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'; 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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AccumulatedOtherComprehensiveIncomeLossNetOfTax" id="Fact_ce487df6de7f42f7b8c77a08d145dc67" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">57,480</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'; 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: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman'; 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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:RetainedEarningsAccumulatedDeficit" id="Fact_e5c1467d48e84e9db875c9a95c317d68" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">1,553,948</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'; 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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:RetainedEarningsAccumulatedDeficit" id="Fact_49f9d5e423964e58bf47306bfe215fd4" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">1,429,625</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'; font-size: 10pt;">)</div>
        </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: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total stockholders&#8217; equity</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquity" id="Fact_7233636d15704723b5b453128bcd0aa4" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">486,570</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:StockholdersEquity" id="Fact_72be79b3d961421696b3c821e00a1f9b" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">572,887</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: 54pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:LiabilitiesAndStockholdersEquity" id="Fact_1ff304ed0ed84581b2d4f5f331ecaa3f" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">2,885,221</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:LiabilitiesAndStockholdersEquity" id="Fact_8ae3d57392c94bea981bfe93b9c946c0" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">2,533,876</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>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">See accompanying notes.</div>

  <div><br />
  </div>

  <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
    <div class="BRPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">3</div>

    </div>

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

    <div class="BRPFPageHeader">
      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"><a id="IncomeStatementQ1"><!--Anchor--></a>IONIS PHARMACEUTICALS, INC.</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">(in thousands, except for per share amounts)</div>

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

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" colspan="6">
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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; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">2023</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 10pt; font-weight: bold;">2022</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;">&#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;">
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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>

  </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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_8ccc59285b1c4fde8c989da3abc6e321" contextRef="c20230101to20230331_ProductOrServiceAxis_SpinrazaRoyaltiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">50,247</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'; 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: -27pt; margin-left: 45pt; color: #000000; font-family: 'Times New Roman'; 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">
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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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_bd9d372310794274aada2c5b2070effc" contextRef="c20220101to20220331_ProductOrServiceAxis_ProductMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">6,160</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: -27pt; margin-left: 45pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_c20de44aa08a4feeb6ec553470e9e55b" contextRef="c20230101to20230331_ProductOrServiceAxis_LicensingAndOtherRoyaltiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">11,043</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_657d26ddec9a4b84ace6ae70602dd9e1" contextRef="c20220101to20220331_ProductOrServiceAxis_LicensingAndOtherRoyaltiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">12,307</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: 45pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_bd6472880fbb416b95f903f2621fca89" contextRef="c20230101to20230331_ProductOrServiceAxis_CommercialMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">67,768</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_94547c1c92ad438eb4bebba69138f6b7" contextRef="c20220101to20220331_ProductOrServiceAxis_CommercialMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">72,285</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'; font-size: 10pt;">Research and development 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'; font-size: 10pt;">Collaborative agreement 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_867fe0ade3e74b7183b2588f9ee7e72b" contextRef="c20230101to20230331_ProductOrServiceAxis_CollaborativeAgreementRevenueMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">38,334</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_ed9b5b2f8b3047b282203f79707f4ee9" contextRef="c20220101to20220331_ProductOrServiceAxis_CollaborativeAgreementRevenueMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">49,784</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; margin-left: 18pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Eplontersen joint development 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_16724ac1f55547198e62e292ce92d841" contextRef="c20230101to20230331_ProductOrServiceAxis_EplontersenJointDevelopmentRevenueMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">24,422</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_baadb9fbcbb548dc9af9b6531ab3da71" contextRef="c20220101to20220331_ProductOrServiceAxis_EplontersenJointDevelopmentRevenueMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">19,850</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%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 45pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total research and development 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_6818c90d3f4340a79eb48f6075623367" contextRef="c20230101to20230331_ProductOrServiceAxis_ResearchAndDevelopmentRevenueMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">62,756</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_9acb8deee3a34c1397a2b1443fc1e129" contextRef="c20220101to20220331_ProductOrServiceAxis_ResearchAndDevelopmentRevenueMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">69,634</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: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_2bf4f3496f6849518a3c8f3f6a217401" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">130,524</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_f84a7b183364428784e980367c723478" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">141,919</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%;">&#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>

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    <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>

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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>

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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%; 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>

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  <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 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%;">&#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: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman'; 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">&#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'; 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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">)</div>
        </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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Other income (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: 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'; font-size: 10pt;">Investment 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: 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: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman'; 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">&#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'; 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'; font-size: 10pt;">)</div>
        </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">
          <div style="color: #000000; font-family: 'Times New Roman'; 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: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Loss 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">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">)</div>
        </td>

  </tr>

  <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">
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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: 76%; 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>

  </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'; font-size: 10pt;">Loss before income tax expense</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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" id="Fact_17d54ee7ad4a4636abf6764960c4d9ba" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">112,943</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'; 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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" id="Fact_017b25bf4b03468a8ac1b73de0c3d606" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">64,071</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'; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; 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>

  </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'; font-size: 10pt;">Income tax expense</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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncomeTaxExpenseBenefit" id="Fact_c5a69d2f02e24e19b6da5f9a18581cdf" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">11,380</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'; 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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncomeTaxExpenseBenefit" id="Fact_2dab61c5ec204491bd1fc811b2bf4fbc" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,094</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'; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; 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>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px;">
          <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;">Net 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'; 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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_93d0327ae14e442a8109ddf312da8fa3" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">124,323</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'; 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'; 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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_dbd0dbd1d4234d58b258352ef6f9c468" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">65,165</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'; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; 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>

  </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'; font-size: 10pt;">Basic and diluted net 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'; 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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:EarningsPerShareDiluted" id="Fact_1aabdd08223b4caebb285f5d916de379" contextRef="c20230101to20230331" unitRef="U004" decimals="2" sign="-" scale="0" format="ixt:num-dot-decimal"><ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_d59214d8ae584a1e957e554c6b39c7eb" contextRef="c20230101to20230331" unitRef="U004" decimals="2" sign="-" scale="0" format="ixt:num-dot-decimal">0.87</ix:nonFraction></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'; 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'; 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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:EarningsPerShareDiluted" id="Fact_8ed197c75da340a3a6411859d57c1e6b" contextRef="c20220101to20220331" unitRef="U004" decimals="2" sign="-" scale="0" format="ixt:num-dot-decimal"><ix:nonFraction name="us-gaap:EarningsPerShareBasic" id="Fact_14f9864fee9249b4a9c5c73faaa62d1b" contextRef="c20220101to20220331" unitRef="U004" decimals="2" sign="-" scale="0" format="ixt:num-dot-decimal">0.46</ix:nonFraction></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'; font-size: 10pt;">)</div>
        </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'; font-size: 10pt;">Shares used in computing basic and diluted net 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:WeightedAverageNumberOfDilutedSharesOutstanding" id="Fact_9f417dae912e4189994eada2a8b2d4f7" contextRef="c20230101to20230331" unitRef="U001" decimals="-3" scale="3" format="ixt:num-dot-decimal"><ix:nonFraction name="us-gaap:WeightedAverageNumberOfSharesOutstandingBasic" id="Fact_cb5b708aa9d54d74894b78084744f61b" contextRef="c20230101to20230331" unitRef="U001" decimals="-3" scale="3" format="ixt:num-dot-decimal">142,735</ix:nonFraction></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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:WeightedAverageNumberOfDilutedSharesOutstanding" id="Fact_0bfcbfda806d43c4bf1a6393fe6973ab" contextRef="c20220101to20220331" unitRef="U001" decimals="-3" scale="3" format="ixt:num-dot-decimal"><ix:nonFraction name="us-gaap:WeightedAverageNumberOfSharesOutstandingBasic" id="Fact_f197f87c51c148d586ce6d486cb242e1" contextRef="c20220101to20220331" unitRef="U001" decimals="-3" scale="3" format="ixt:num-dot-decimal">141,599</ix:nonFraction></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>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">See accompanying notes.</div>

  <div><br />
  </div>

  <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
    <div class="BRPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">4</div>

    </div>

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

    <div class="BRPFPageHeader">
      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"><a id="ComprehensiveIncomeQ1"><!--Anchor--></a>IONIS PHARMACEUTICALS, INC.</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">CONDENSED CONSOLIDATED STATEMENTS OF COMPREHENSIVE LOSS</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">(in thousands)</div>

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

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; 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'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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'; font-size: 10pt; font-weight: bold;">2023</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'; font-size: 10pt; font-weight: bold;">2022</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">&#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;">&#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: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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'; font-size: 10pt;">)</div>
        </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>

    <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'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Currency translation adjustment</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax" id="Fact_8c488c3b36034e08aa370c9ffb2c6875" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">104</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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax" id="Fact_3d7f7690411649a3a532188469a6cbe2" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">154</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'; font-size: 10pt;">)</div>
        </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%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Comprehensive loss</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'; 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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:ComprehensiveIncomeNetOfTax" id="Fact_49ad4947efda47a8b9b2ba8b913e17fd" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">115,826</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'; 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'; 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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:ComprehensiveIncomeNetOfTax" id="Fact_2b15cd4eb3be402a951f50cf88199c7f" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">81,075</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'; font-size: 10pt;">)</div>
        </td>

  </tr>


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

  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">See accompanying notes.</div>

  <div><br />
  </div>

  <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
    <div class="BRPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">5</div>

    </div>

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

    <div class="BRPFPageHeader">
      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"><a id="EquityQ1"><!--Anchor--></a>IONIS PHARMACEUTICALS, INC.</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">CONDENSED CONSOLIDATED STATEMENTS OF STOCKHOLDERS</span>&#8217;<span style="font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"> EQUITY</span></div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">(In thousands)</div>

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

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 9pt; font-weight: bold;">Common Stock</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 9pt; font-weight: bold;">Additional</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 9pt; font-weight: bold;">Accumulated Other</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 9pt; font-weight: bold;">Accumulated</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 9pt; font-weight: bold;">Total</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 9pt;"><span style="font-family: 'Times New Roman'; font-size: 9pt; 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'; font-size: 9pt; 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; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 9pt; font-weight: bold;">Shares</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 9pt; font-weight: bold;">Amount</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 9pt; font-weight: bold;">Paid in Capital</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 9pt; font-weight: bold;">Comprehensive Loss</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 9pt; font-weight: bold;">Deficit</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 9pt; 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: 28%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 9pt; font-weight: bold;">Balance at <span style="text-indent: 0pt;">December 31, 2021</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:SharesIssued" id="Fact_3a9555e88e8e4073b9ff1cc051b93040" contextRef="c20211231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:num-dot-decimal">141,210</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'; font-size: 9pt;">$</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_f460bd0aff664980870ea8e5e75a1848" contextRef="c20211231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">141</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'; font-size: 9pt;">$</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_d4889378c8d9480b96b3dc528f1eba37" contextRef="c20211231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 9pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
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        </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">
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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'; font-size: 9pt;">$</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>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 28%;">
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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>

    <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'; font-size: 9pt;">)</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">
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        </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'; font-size: 9pt;">Change in unrealized losses, 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: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 9pt;">&#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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 9pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" id="Fact_8934ac53e1df4f7489c4b96df024b26e" contextRef="c20220101to20220331_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 9pt;">)</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" id="Fact_45dd7d43b503464f9f0b0c364cd2be8a" contextRef="c20220101to20220331_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 9pt;">(<ix:nonFraction name="us-gaap:OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" id="Fact_9e658ea9c0dc4a56b7e313426cab56aa" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">15,756</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'; font-size: 9pt;">)</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'; font-size: 9pt;">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: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 9pt;">&#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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax" id="Fact_d1aabbaae81446b0914967d0f2a70b44" contextRef="c20220101to20220331_StatementEquityComponentsAxis_CommonStockMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax" id="Fact_a80b5f0672584087b5268c8be3599f13" contextRef="c20220101to20220331_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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>

    <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'; font-size: 9pt;">)</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax" id="Fact_79cf286844754eb2849b8aa2a0d7b9d1" contextRef="c20220101to20220331_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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>

    <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'; font-size: 9pt;">)</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'; font-size: 9pt;">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: 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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:StockIssuedDuringPeriodValueShareBasedCompensationGross" id="Fact_18e6b18461214b95a98ece00932a9e6d" contextRef="c20220101to20220331_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,848</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:StockIssuedDuringPeriodValueShareBasedCompensationGross" id="Fact_a4b0547c37454b19887e01e8f1ee7eee" contextRef="c20220101to20220331_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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 valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; 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: 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>

    <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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 9pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" id="Fact_ea1d443af1494feeb9c969facd4cd97a" contextRef="c20220101to20220331_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" id="Fact_6698c6866b274e68b2b91954263cd3ea" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">26,236</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: 28%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 9pt;">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: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 9pt;">(<ix:nonFraction name="us-gaap:SharesPaidForTaxWithholdingForShareBasedCompensation" id="Fact_ac49bd555f144f029bdd210f735a40fb" contextRef="c20220101to20220331_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:num-dot-decimal">304</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'; font-size: 9pt;">)</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_0fc266ecc4bd487887964edef819ccee" contextRef="c20220101to20220331_StatementEquityComponentsAxis_CommonStockMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 9pt;">(<ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_cfd0b9aef082475bb135e7948156a230" contextRef="c20220101to20220331_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">9,173</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'; font-size: 9pt;">)</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_13d3315dc3ac4af9ae4aba8d66c37b5e" contextRef="c20220101to20220331_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_460f2204ce2f415da66d28cc409db981" contextRef="c20220101to20220331_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 9pt;">(<ix:nonFraction name="us-gaap:AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation" id="Fact_0220268ecf7f4685a7724adf552aebbc" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">9,173</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'; font-size: 9pt;">)</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'; font-size: 9pt; font-weight: bold;">Balance at <span style="text-indent: 0pt;">March 31, 2022</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:SharesIssued" id="Fact_ba38bc2ac6c549c19380cdd7d23a7644" contextRef="c20220331_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:num-dot-decimal">141,753</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'; font-size: 9pt;">$</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_44f1c20930ab40a4840b6a493c0c1c0d" contextRef="c20220331_StatementEquityComponentsAxis_CommonStockMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">142</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'; font-size: 9pt;">$</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_8e3ae95fed3948e6aa338f7bcc06a024" contextRef="c20220331_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,983,078</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'; font-size: 9pt;">$</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'; font-size: 9pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_98d86fa0ae7f464e860e56b84513348e" contextRef="c20220331_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">48,578</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'; font-size: 9pt;">)</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'; font-size: 9pt;">$</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'; font-size: 9pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_1609172481c04b6fae591dd8d4ed670c" contextRef="c20220331_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">1,225,068</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'; font-size: 9pt;">)</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'; font-size: 9pt;">$</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_a23dd4b0f79747e6a869f76130e772d5" contextRef="c20220331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">709,574</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>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 28%; 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>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; 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: 28%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 9pt; font-weight: bold;">Balance at <span style="text-indent: 0pt;">December 31, 2022</span></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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:SharesIssued" id="Fact_32f887af1f384adf8f9fd2b14798a9dc" contextRef="c20221231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:num-dot-decimal">142,058</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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 9pt;">$</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'; font-size: 9pt;">$</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_d729ddf413884aada9a66c8ba510ae4d" contextRef="c20221231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">2,059,850</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'; font-size: 9pt;">$</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'; font-size: 9pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_e2545d09515d4485b16e0683e731851a" contextRef="c20221231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">57,480</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'; font-size: 9pt;">)</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'; font-size: 9pt;">$</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'; font-size: 9pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_21ce6f0e307d4eb7ba78a66d3da6e84d" contextRef="c20221231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">1,429,625</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'; font-size: 9pt;">)</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'; font-size: 9pt;">$</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_7648bfdfbf0940a4bf96a7ce13cf1ad3" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">572,887</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>

  </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; font-family: 'Times New Roman'; font-size: 9pt;">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: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 9pt;">&#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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_c88d54dc726342e4972eaefd7a051920" contextRef="c20230101to20230331_StatementEquityComponentsAxis_CommonStockMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_9cf891be08ec4be38cb74bb1f2b5f043" contextRef="c20230101to20230331_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_cdc09fc9cea84c4bb56bf39a0b0f0bb2" contextRef="c20230101to20230331_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 9pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_35a1e22e0a16468e980e52ec905cdd6e" contextRef="c20230101to20230331_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">124,323</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'; font-size: 9pt;">)</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'; font-size: 9pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_f3fb7df78ee84b679a9455a24c8868ed" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">124,323</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'; font-size: 9pt;">)</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'; font-size: 9pt;">Change in unrealized gains, 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: 9%;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 9pt;">&#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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" id="Fact_11314cebb76149f4a608afac24ac04b8" contextRef="c20230101to20230331_StatementEquityComponentsAxis_CommonStockMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" id="Fact_7b0eb56cbf6c4876adbb9cd78cb7fab3" contextRef="c20230101to20230331_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" id="Fact_e9bf727feb074c6d81eadada30431fc1" contextRef="c20230101to20230331_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">8,393</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" id="Fact_4f7972f7ccc845178dd50c3adeba7bea" contextRef="c20230101to20230331_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" id="Fact_c166701bbeab4dc6b0ef6b9ba9449b64" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">8,393</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: 28%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 9pt;">Foreign currency translation</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'; font-size: 9pt;">&#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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax" id="Fact_227d758ea4e74df1a393442ec610b305" contextRef="c20230101to20230331_StatementEquityComponentsAxis_CommonStockMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax" id="Fact_0b254bcc6c334e83b0fc2405839bb29a" contextRef="c20230101to20230331_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax" id="Fact_59f8cd0035bf41978b1986a44e2b9b77" contextRef="c20230101to20230331_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">104</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax" id="Fact_e0d9b726e3a74e96bb34879db9ea1ac5" contextRef="c20230101to20230331_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax" id="Fact_3ea72a4068e947c39ec89e6e3d5e6026" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">104</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: 28%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 9pt;">Issuance of common stock in connection with employee stock plans</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:StockIssuedDuringPeriodSharesShareBasedCompensation" id="Fact_a0997c97f0564e8ebfa4ae2be270a0ee" contextRef="c20230101to20230331_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:num-dot-decimal">965</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="vertical-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="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: 28%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 9pt;">Stock-based compensation 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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 9pt;">&#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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" id="Fact_68081df6527740dfa26ec4797ec27aa4" contextRef="c20230101to20230331_StatementEquityComponentsAxis_CommonStockMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" id="Fact_5314ac973db348bb85730f2174126923" contextRef="c20230101to20230331_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">26,948</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" id="Fact_2b2724fdff53416ba79dd482f9ac014a" contextRef="c20230101to20230331_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" id="Fact_9b47baa9611d4ccbb269f9f88ab523c8" contextRef="c20230101to20230331_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" id="Fact_469cc0df4f854f08ad045ffae103da1d" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">26,948</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: 28%; padding-bottom: 4px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 9pt; font-weight: bold;">Balance at <span style="text-indent: 0pt;">March 31, 2023</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:SharesIssued" id="Fact_0f0be876932540309deb6071f37c6b70" contextRef="c20230331_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3" scale="3" format="ixt:num-dot-decimal">143,023</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'; font-size: 9pt;">$</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_b71c12ae90734864a4463846ddf4a35f" contextRef="c20230331_StatementEquityComponentsAxis_CommonStockMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">143</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'; font-size: 9pt;">$</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_f4b8bbee549b4d698629eeec3f6d69bc" contextRef="c20230331_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">2,089,358</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'; font-size: 9pt;">$</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'; font-size: 9pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_b92a64b7192841d0ad0df25703888391" contextRef="c20230331_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">48,983</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'; font-size: 9pt;">)</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'; font-size: 9pt;">$</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'; font-size: 9pt;">(<ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_1599b9afeae3443694982451aff023a8" contextRef="c20230331_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">1,553,948</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'; font-size: 9pt;">)</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'; font-size: 9pt;">$</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'; font-size: 9pt;"><ix:nonFraction name="us-gaap:StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" id="Fact_e457c14215284c388c791e447980f51c" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">486,570</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>
  <div><br />
  </div>

  <div><br />
  </div>

  <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">See accompanying notes.</div>

  <div><br />
  </div>

  <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
    <div class="BRPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">6</div>

    </div>

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

    <div class="BRPFPageHeader">
      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

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

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">CONDENSED CONSOLIDATED STATEMENTS OF CASH FLOWS</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">(in thousands)</div>

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

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">2023</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 10pt; font-weight: bold;">2022</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">&#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: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">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>

  </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'; 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">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_f7c36546ee144c2c86ebae7331367498" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">124,323</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'; 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">
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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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:NetIncomeLoss" id="Fact_a21016941dc0429abc056d42872b32b2" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">65,165</ix:nonFraction></div>
        </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: 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">&#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'; 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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:nonFraction name="us-gaap:Depreciation" id="Fact_100d69cecae84cbdad6e81cc7ef52262" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">2,604</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:Depreciation" id="Fact_8c77ba4be59247e38c94131c141d0abf" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">3,701</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%;">
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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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:OperatingLeaseRightOfUseAssetAmortizationExpense" id="Fact_9e6711269ac449af9f3ea5cf3d5eaa6a" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">2,395</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:OperatingLeaseRightOfUseAssetAmortizationExpense" id="Fact_5558af291e4642f9823614e737f072ce" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">602</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'; font-size: 10pt;">Amortization of other 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">&#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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AmortizationOfIntangibleAssets" id="Fact_edc8ad178aa7466a8d83a15fca3ea881" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">607</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AmortizationOfIntangibleAssets" id="Fact_f8039ed914974946804216d314447463" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">592</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'; 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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AccretionAmortizationOfDiscountsAndPremiumsInvestments" id="Fact_246d1c45e9574034a56b56918f85ebb2" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">5,042</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AccretionAmortizationOfDiscountsAndPremiumsInvestments" id="Fact_4aaed7ae1baf412b9dbc761309827e6d" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">4,175</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'; font-size: 10pt;">Amortization of 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">&#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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AmortizationOfFinancingCosts" id="Fact_0996ae3cb47d4deda2a70a7fe98905e0" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,486</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AmortizationOfFinancingCosts" id="Fact_0c9f58357fb646578e9fa6d8e42f1be2" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,343</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'; font-size: 10pt;">Non-cash interest related to sale of future royalties</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'; font-size: 10pt;"><ix:nonFraction name="ions:InterestExpenseRelatedToSaleOfFutureRoyalties" id="Fact_086bf64fac6b4680b15353ddeab54f26" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">15,363</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'; font-size: 10pt;"><ix:nonFraction name="ions:InterestExpenseRelatedToSaleOfFutureRoyalties" id="Fact_e2859b6b5908454a9501ba4b33770396" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman'; 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: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:nonFraction name="us-gaap:ShareBasedCompensation" id="Fact_04aaa2990d5a40ad8fdb1b5232b70a08" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">26,948</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:ShareBasedCompensation" id="Fact_75990e27c7ef4862aef11ff7e8db6961" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">26,236</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'; font-size: 10pt;">Loss (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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RealizedInvestmentGainsLosses" id="Fact_14350362b48c4c63a2d02245c7bdfc8e" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">529</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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:RealizedInvestmentGainsLosses" id="Fact_1d0b4f23d12a4c8d93769c2560a353b7" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">10</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'; font-size: 10pt;">)</div>
        </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'; font-size: 10pt;">Non-cash losses related to disposal 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:GainLossOnDispositionOfAssets" id="Fact_01a5dec9e9674dcc9254b9bfa6e79949" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:GainLossOnDispositionOfAssets" id="Fact_9e5576dfce9c47598f395f576a1839a2" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">527</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'; font-size: 10pt;">Non-cash losses related to other 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:ImpairmentOfIntangibleAssetsFinitelived" id="Fact_7fcd200b638b455db39131034fdc6876" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">445</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:ImpairmentOfIntangibleAssetsFinitelived" id="Fact_fe5c9b55fb8549bebb24e58da0204a34" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">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: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman'; 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>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
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    <td valign="bottom" style="vertical-align: bottom; width: 1%;" 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>

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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>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
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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>

    <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%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Accounts payable</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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        </td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: 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: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Accrued compensation</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">
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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">
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  <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'; font-size: 10pt;">Accrued liabilities and other 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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncreaseDecreaseInOtherCurrentLiabilities" id="Fact_08f6c9cf45f246f6a33cd0c9749cb737" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">28,460</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'; 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: 76%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncreaseDecreaseInContractWithCustomerLiability" id="Fact_5d444769c22d417199294bd747e46936" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">13,037</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'; 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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:IncreaseDecreaseInContractWithCustomerLiability" id="Fact_7536a4e7a5c548658c9c6c4190e7e76b" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" sign="-" format="ixt:num-dot-decimal">25,018</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'; font-size: 10pt;">)</div>
        </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: 54pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Net cash used in operating activities</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'; 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">
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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'; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; 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>

  </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'; font-size: 10pt; font-weight: bold;">Investing 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>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 36pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:PaymentsToAcquireAvailableForSaleSecuritiesDebt" id="Fact_083200534ca3433a9d3c58296e5b5402" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">688,278</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'; 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">
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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
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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: 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">
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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; 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">
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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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  </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 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: 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'; font-size: 10pt;">)</div>
        </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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Financing activities:</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%;">
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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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:nonFraction name="us-gaap:ProceedsFromIssuanceOfSharesUnderIncentiveAndShareBasedCompensationPlansIncludingStockOptions" id="Fact_8bffc0bd215e4f839416df4a6531312e" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,848</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: -9.15pt; margin-left: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock
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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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%;">
          <div style="text-align: left; text-indent: -9.15pt; margin-left: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Proceeds from sale of future royalties</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'; font-size: 10pt;"><ix:nonFraction name="ions:ProceedsFromSaleOfFutureRoyalties" id="Fact_392a7724834945959f015a174a594118" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9.15pt; margin-left: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Payments of transaction costs related to sale of future 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">&#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'; 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: 76%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9.15pt; margin-left: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Principal payments on mortgage debt</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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:RepaymentsOfSecuredDebt" id="Fact_95b149e4b1f949d691d01b7a972215e2" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">39</ix:nonFraction></div>
        </td>

    <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>

    <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: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 54pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Net cash provided by (used in) financing activities</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>

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    <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;">
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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: 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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">
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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: 76%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Cash and cash equivalents at beginning of period</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" id="Fact_f005ffe7399e4372b86484b39e4de899" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">276,472</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" id="Fact_6c5f411c5f5446ed84bf5042679097db" contextRef="c20211231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">869,191</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: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Cash and cash equivalents at end of period</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" id="Fact_22fc70baf81348a4bed7f3a0cca2d925" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">309,031</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" id="Fact_26348b07f1404eb2b971660219ce0e2f" contextRef="c20220331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">542,513</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: 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Supplemental disclosures of cash flow information:</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: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Interest paid</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:InterestPaidNet" id="Fact_1c0954c400a1482b8ec42df7704e2f57" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">89</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:InterestPaidNet" id="Fact_99a9e46f9bbe4846a09670f406e934e7" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">594</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: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Income taxes 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:IncomeTaxesPaid" id="Fact_e1a1dc9fdd464c8d8c36512a7e6251fb" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">293</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:IncomeTaxesPaid" id="Fact_85ce33dc7db749c6bac7ae7eadc1d4ee" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">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: 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Supplemental disclosures of non-cash investing and financing activities:</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: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Amounts accrued for capital and patent expenditures</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'; 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'; font-size: 10pt;"><ix:nonFraction name="ions:NonCashCapitalAndPatentExpenditures" id="Fact_e747862ab08345fcae14d5a69abc90c7" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">3,058</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'; 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'; font-size: 10pt;"><ix:nonFraction name="ions:NonCashCapitalAndPatentExpenditures" id="Fact_b758276d9ff04fe0a8e9a80dd38bfae6" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,344</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>
  <div><br />
  </div>

  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">See accompanying notes.</div>

  <div><br />
  </div>

  <div><br />
  </div>

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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

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

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">NOTES TO CONDENSED CONSOLIDATED FINANCIAL STATEMENTS</div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 31, 2023</div>

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

  <div><br />
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<div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">1.&#160; Organization and Basis of Presentation</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Organization and Business Activity</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">We incorporated in California on January 10, 1989. In conjunction with our initial public offering, we reorganized as a Delaware corporation in April
    1991. We are a leader in the discovery and development of RNA-targeted therapeutics.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Basis of Presentation</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We prepared the unaudited interim condensed consolidated financial statements for the three months ended&#160;March 31, 2023 and 2022 on the same basis as the audited financial statements for the year ended December 31, 2022. We included all normal recurring adjustments in the financial statements, which we considered necessary for a fair presentation of our financial position at such dates and our
    operating results and cash flows for those periods. Our operating results for the interim periods may not be indicative of what our operating results will be for the entire year. For more complete financial information, these financial statements, and
    notes thereto, should be read in conjunction with the audited financial statements for the year ended December 31, 2022 included in our Annual
    Report on Form 10-K filed with the Securities and Exchange Commission, or SEC.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">In our condensed consolidated financial statements, we included the accounts of Ionis Pharmaceuticals, Inc. and the consolidated
    results of our wholly owned subsidiary, Akcea Therapeutics, Inc. and its wholly owned subsidiaries (&#8220;we&#8221;, &#8220;us&#8221; or &#8220;our&#8221;).</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We operate as a <span style="-sec-ix-hidden:Fact_d751d8638e404708bbf18fb6bb90a9f5">single</span>
    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_baf534ae803246ddb035eb980683637d">single</span>
    operating segment.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Use of Estimates</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">We prepare our condensed consolidated financial statements in conformity
      with accounting principles generally accepted in the United States, or </span>U.S., that require us to make estimates and assumptions that affect the amounts reported in our condensed consolidated financial statements and accompanying notes. Actual
    results could differ from our estimates.</div>
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<div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">2.&#160; Significant Accounting Policies</div>
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<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Our significant accounting policies have not changed substantially from those included in our Annual Report on Form 10-K for the year ended
    December 31, 2022, other than as discussed below.</div>
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<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Liability Related to Sale of Future Royalties</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">In January 2023, we entered into a royalty purchase agreement with Royalty Pharma Investments, or Royalty Pharma, to monetize a portion
    of our future SPINRAZA and pelacarsen royalties we are entitled to under our arrangements with Biogen and Novartis, respectively. Refer to Note 10, <span style="font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;">Liability Related to
      Sale of Future Royalties</span>, for further details on the agreement.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We record upfront payments and milestone payments we receive from the sale of future royalties as a liability, net of transaction costs.
    We record royalty payments made to Royalty Pharma as a reduction of the liability and amortize the transaction costs over the estimated life of the related royalty stream. We account for the associated interest expense under the effective interest rate
    method, while continuing to recognize the full amount of royalty revenue in the period in which the counterparty sells the related product and recognizes the related revenue.</div>
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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">The liability related to the sale of future royalties, effective interest rate and the related interest expense are calculated using our
    current estimate of anticipated future royalty payments under the arrangement, which we periodically reassess based on internal projections and information from our partners who are responsible for commercializing the medicines. If there is a material
    change in our estimate, we will prospectively adjust the liability related to the sale of future royalties, effective interest rate and the related interest expense.</div>
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<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Recently Adopted Accounting Standards</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We do not expect any recently issued accounting standards to have a material impact to our financial results.</div>
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<div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">3. Supplemental Financial Data</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Our inventory consisted of the following (in thousands):</div>
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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 31, 2023</div>
        </td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">December 31, 2022</div>
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          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Raw materials:</div>
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          <div style="text-align: justify; text-indent: -9pt; margin-left: 19.4pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Raw materials - clinical</div>
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    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

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          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
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          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:nonFraction name="us-gaap:InventoryRawMaterials" id="Fact_3043726b7f0d40479abbe8c68900b93f" contextRef="c20230331_PublicUtilitiesInventoryAxis_ClinicalRawMaterialsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">17,356</ix:nonFraction></div>
        </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">
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    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; white-space: nowrap;">
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        </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">
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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; 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">
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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: 76%; background-color: #CCEEFF; white-space: nowrap;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total raw materials</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">
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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; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:InventoryRawMaterials" id="Fact_e3f1efde1cdb414796dec720e17eac54" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">19,760</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>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; white-space: nowrap;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Work in process</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:InventoryWorkInProcess" id="Fact_e7c4b729eb5c4047a12ddaf1f657b647" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,840</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%; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:InventoryWorkInProcess" id="Fact_182d548d120f4e1daae74044c3e1bbe5" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">2,109</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>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF; white-space: nowrap;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Finished goods</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:InventoryFinishedGoods" id="Fact_b21c128f10e14f89b4963ecd92676ea1" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">218</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; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:InventoryFinishedGoods" id="Fact_70a3a016ecb849cd9021230823cf224d" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">164</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%; padding-bottom: 4px; white-space: nowrap;">
          <div style="text-align: justify; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total inventory</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:InventoryNet" id="Fact_6f6a7ebaae1b4d95ace7fcfcf1fba210" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">22,200</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; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:InventoryNet" id="Fact_3e4c02edf53745679ae7e698216e7837" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">22,033</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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<div style="text-align: left; font-family: Calibri; font-size: 12pt;"><br />
  </div>
</ix:continuation>
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<div style="display:none;"><br /></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Accrued Liabilities</div>
</ix:nonNumeric></ix:continuation>
  <ix:continuation id="Text_7c9cf20b293142939c12ab1a83a4497f9" continuedAt="Text_7c9cf20b293142939c12ab1a83a4497f10"><ix:continuation id="Text_e45ebaa9907241f69e8d4ddaca3a5a8e1" continuedAt="Text_e45ebaa9907241f69e8d4ddaca3a5a8e2">
<div><br />
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  <ix:continuation id="Text_7c9cf20b293142939c12ab1a83a4497f10" continuedAt="Text_7c9cf20b293142939c12ab1a83a4497f11"><ix:continuation id="Text_e45ebaa9907241f69e8d4ddaca3a5a8e2" continuedAt="Text_e45ebaa9907241f69e8d4ddaca3a5a8e3">
<div style="display:none;"><br /></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">Our accrued liabilities consisted of the following (in thousands):</div>
</ix:continuation></ix:continuation>
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<div><br />
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  <ix:continuation id="Text_7c9cf20b293142939c12ab1a83a4497f12"><ix:continuation id="Text_e45ebaa9907241f69e8d4ddaca3a5a8e4">
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    <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;">

        </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;" 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; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">December 31, 2022</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; white-space: nowrap;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Clinical development expenses</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'; 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'; font-size: 10pt;"><ix:nonFraction name="ions:AccruedClinicalDevelopmentExpenses" id="Fact_9fa65e9eb4874e529d2b5a8558dbeefc" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">85,694</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'; 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'; font-size: 10pt;"><ix:nonFraction name="ions:AccruedClinicalDevelopmentExpenses" id="Fact_e1554d35bd0e4c82aabac0d765ba6ddc" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">116,460</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: 76%; white-space: nowrap;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">In-licensing expenses</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'; font-size: 10pt;"><ix:nonFraction name="ions:AccruedInLicensingFeesCurrent" id="Fact_c222f622055145968e8cd08ff3a569bd" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">12,704</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%; 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'; font-size: 10pt;"><ix:nonFraction name="ions:AccruedInLicensingFeesCurrent" id="Fact_7076c86dd1604e5a826b9716b8c0ca6e" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">7,945</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; white-space: nowrap;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Commercial expenses</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'; font-size: 10pt;"><ix:nonFraction name="ions:AccruedCommercialExpensesCurrent" id="Fact_74d1a19cf230440593ea60ac85e2acd3" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">4,704</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">&#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'; font-size: 10pt;"><ix:nonFraction name="ions:AccruedCommercialExpensesCurrent" id="Fact_0c409149156e4e1bb3090f026e0406df" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">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: 76%; padding-bottom: 2px; white-space: nowrap;">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Other miscellaneous expenses</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%; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherAccruedLiabilitiesCurrent" id="Fact_9ed0b35c739e48bbb51027c4ea2073ae" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">9,600</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; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:OtherAccruedLiabilitiesCurrent" id="Fact_b95beacb8e88464e9674b3d0a46cdaf4" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">12,198</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; white-space: nowrap;">
          <div style="text-align: justify; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total accrued liabilities</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%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AccruedLiabilitiesCurrent" id="Fact_eda2e67f42534d11b5f9b63e05969ad1" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">112,702</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; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AccruedLiabilitiesCurrent" id="Fact_e41fd559b7f64fab9ce5f7f42569b6db" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">140,101</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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  </div>
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<div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">4.&#160; Collaborative Arrangements and Licensing Agreements</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 11pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt;">Below, we have included our Biogen and GSK collaborations, which are our
      only collaborations with substantive changes during 2023 from those included in Part IV, Item 15, Note 7 of our audited financial statements
      included in our Annual Report on Form 10-K for the year ended December 31, 2022.</span></div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic; font-weight: bold;">Biogen</div>
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  </div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">We have several strategic collaborations with Biogen focused on using
      antisense technology to advance the treatment of neurological disorders. We developed and licensed to Biogen SPINRAZA, our approved medicine to treat people with spinal muscular atrophy, or SMA. Under our 2013 strategic neurology collaboration,
      Biogen developed QALSODY (tofersen), our recently approved medicine to treat people with superoxide dismutase 1 amyotrophic lateral sclerosis, or SOD1-ALS. We and Biogen are currently developing numerous investigational medicines to treat
      neurodegenerative diseases under these collaborations, including medicines in development to treat people with </span>amyotrophic lateral sclerosis, or ALS<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">, SMA, Angelman
      Syndrome, Alzheimer&#8217;s disease</span><sub style="color: #000000;">&#160;</sub><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">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 </span>March 31, 2023<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">, we have received more than $</span><ix:nonFraction name="ions:CumulativePaymentsReceived" id="Fact_4de0101278b94f98a15dfb2c4990f91e" contextRef="c20230331_RangeAxis_MinimumMember_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U002" decimals="-8" scale="9" format="ixt:num-dot-decimal">3.5</ix:nonFraction><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> billion in payments from our Biogen collaborations.</span></div>
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    <div class="BRPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">9</div>

    </div>

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

    <div class="BRPFPageHeader">
      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">In the first quarter of 2023, we earned a $<ix:nonFraction name="ions:MilestonePaymentEarnedAndRecognizedAsRevenueAsServicesArePerformed" id="Fact_d1f09be6886d40358705c508646cb80e" contextRef="c20230101to20230331_TypeOfArrangementAxis_BiogenCollaboration2012NeurologyMember" unitRef="U002" decimals="-6" scale="6" format="ixt:num-dot-decimal">10</ix:nonFraction>
    million milestone payment from Biogen when we advanced ION582 under our 2012 neurology collaboration. We will recognize revenue as we perform services based on our effort to satisfy our research and development, or R&amp;D, services performance
    obligation relative to the total effort expected to satisfy our performance obligation for ION582. We will achieve the next payment of up to $<ix:nonFraction name="ions:NextPaymentToBeAchieved" id="Fact_a91583b7e9f34be6a33512e4083d6fe9" contextRef="c20230331_RangeAxis_MaximumMember_TypeOfArrangementAxis_BiogenCollaboration2012NeurologyMember" unitRef="U002" decimals="-6" scale="6" format="ixt:num-dot-decimal">25</ix:nonFraction>
    million if Biogen advances another medicine under our 2012 neurology collaboration.</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'; font-size: 10pt;">During the three months ended March 31, 2023 and 2022, we earned the following revenue from our relationship with Biogen (in thousands, except percentage amounts):</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;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; white-space: nowrap;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">2023</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 10pt; font-weight: bold;">2022</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: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">SPINRAZA royalties (commercial 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_41e0020d7d8b43339e3f6ecab17d7549" contextRef="c20230101to20230331_ProductOrServiceAxis_SpinrazaRoyaltiesMember_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">50,247</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_5a52392df50a40499cfba0408a22a2f9" contextRef="c20220101to20220331_ProductOrServiceAxis_SpinrazaRoyaltiesMember_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">53,818</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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_0e1cf07aa39a4946b68c62a5e677810b" contextRef="c20230101to20230331_ProductOrServiceAxis_ResearchAndDevelopmentRevenueMember_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">20,254</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_2caf9f3dcea84407a99faf8bb7291e67" contextRef="c20220101to20220331_ProductOrServiceAxis_ResearchAndDevelopmentRevenueMember_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">40,049</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>

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  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_e2c83a92da2e4d998a4c975dfa7ee4b5" contextRef="c20230101to20230331_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">70,501</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_65f56aa48fa84183a5efd3c8ab1ce904" contextRef="c20220101to20220331_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">93,867</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: 27pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConcentrationRiskPercentage1" id="Fact_2378a184258a4c21b0f8a03a2ce4c8e8" contextRef="c20230101to20230331_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConcentrationRiskPercentage1" id="Fact_f9f72233c43a478a849fb1b7ab1a524e" contextRef="c20220101to20220331_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">66</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'; font-size: 10pt;">%</div>
        </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; font-family: 'Times New Roman'; font-size: 10pt;">In April 2023, we earned a $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_b9a0d997c9584ac9904f44543846b19f" contextRef="c20230401to20230430_ProductOrServiceAxis_TofersenMember_SubsequentEventTypeAxis_SubsequentEventMember_TypeOfArrangementAxis_BiogenCollaboration2013StrategicNeurologyMember" unitRef="U002" decimals="-6" scale="6" format="ixt:num-dot-decimal">16</ix:nonFraction> million
    milestone payment from Biogen when the FDA approved Biogen&#8217;s New Drug Application, or NDA, for QALSODY. We will achieve the next payment of up to $<ix:nonFraction name="ions:NextPaymentToBeAchieved" id="Fact_4c5fe56f5e154cfd9e5d46579f6dcacd" contextRef="c20230430_RangeAxis_MaximumMember_SubsequentEventTypeAxis_SubsequentEventMember_TypeOfArrangementAxis_BiogenCollaboration2013StrategicNeurologyMember" unitRef="U002" decimals="-6" scale="6" format="ixt:num-dot-decimal">20</ix:nonFraction>
    million if Biogen advances a medicine under the 2013 strategic neurology collaboration.</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; font-family: 'Times New Roman'; font-size: 10pt;">Our condensed consolidated balance sheets at March 31, 2023 and December 31, 2022<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">&#160;</span>included
    deferred revenue of $<ix:nonFraction name="us-gaap:ContractWithCustomerLiability" id="Fact_06b0d8db296b4fe5923cb8d67d6c5f8a" contextRef="c20230331_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">340.9</ix:nonFraction> million and $<ix:nonFraction name="us-gaap:ContractWithCustomerLiability" id="Fact_9e226e0b46f94da29b560891abc17b11" contextRef="c20221231_TypeOfArrangementAxis_BiogenCollaborationsMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">351.2</ix:nonFraction>
    million, respectively, from our relationship with Biogen.</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'; font-size: 10pt; font-style: italic; font-weight: bold;">GSK</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'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">In March 2010, we entered into a collaboration 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. Our collaboration with GSK currently includes bepirovirsen,
      our medicine in development targeting hepatitis B virus, or HBV. We designed this medicine 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</span>. From inception through March 31, 2023, we have received more than $<ix:nonFraction name="ions:CumulativePaymentsReceived" id="Fact_7474537679264fa190413b5b4cc5794a" contextRef="c20230331_RangeAxis_MinimumMember_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" unitRef="U002" decimals="-6" scale="6" format="ixt:num-dot-decimal">105</ix:nonFraction> million in an upfront payment and payments related to the HBV program.</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'; font-size: 10pt;">In the first quarter of 2023, we earned a $<ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_68aa64be027047d68b29c0f6347a9332" contextRef="c20230101to20230331_ProductOrServiceAxis_BepirovirsenMember_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" unitRef="U002" decimals="-6" scale="6" format="ixt:num-dot-decimal">15</ix:nonFraction>
    million milestone payment when GSK initiated a Phase 3 program of bepirovirsen. We recognized this milestone payment as R&amp;D revenue in full in the first quarter of 2023 because we did not have any remaining performance obligations related to the
    milestone payment. We will achieve the next payment of $<ix:nonFraction name="ions:NextPaymentToBeAchieved" id="Fact_f644fbc95b9f4293aac011fc8df1d582" contextRef="c20230331_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" unitRef="U002" decimals="-6" scale="6" format="ixt:num-dot-decimal">15</ix:nonFraction> million if the FDA accepts an NDA filing of bepirovirsen for review.</div>
</ix:continuation>
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<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_1708675790794852a668c0f19c6e176f24" continuedAt="Text_1708675790794852a668c0f19c6e176f25"><ix:nonNumeric name="us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock" id="Text_5ee03dee72e140f5982cf099080fd2ee" contextRef="c20230101to20230331_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" escape="true" continuedAt="Text_dda57d9ff6f4448f9518aafb2c354cbb1">
<div style="display:none;"><br /></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">During the three months ended March 31, 2023 and 2022, we earned the following revenue from our relationship with GSK (in thousands, except percentage amounts):</div>
</ix:nonNumeric></ix:continuation>
  <ix:continuation id="Text_1708675790794852a668c0f19c6e176f25" continuedAt="Text_1708675790794852a668c0f19c6e176f26"><ix:continuation id="Text_dda57d9ff6f4448f9518aafb2c354cbb1" continuedAt="Text_dda57d9ff6f4448f9518aafb2c354cbb2">
<div><br />
  </div>
</ix:continuation></ix:continuation>
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<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

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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'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">2023</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 10pt; font-weight: bold;">2022</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: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_e1d6c580e1374388b381018585988134" contextRef="c20230101to20230331_ProductOrServiceAxis_ResearchAndDevelopmentRevenueMember_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">15,000</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:RevenueFromContractWithCustomerExcludingAssessedTax" id="Fact_8f71225757384089b3ba90a66b883f76" contextRef="c20220101to20220331_ProductOrServiceAxis_ResearchAndDevelopmentRevenueMember_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConcentrationRiskPercentage1" id="Fact_2dc4d339439149bc93ef65f5edd3cb21" contextRef="c20230101to20230331_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">11</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:ConcentrationRiskPercentage1" id="Fact_567b20c3b6984fa2b1b9552945c5c379" contextRef="c20220101to20220331_ConcentrationRiskByBenchmarkAxis_RevenueFromContractWithCustomerMember_ConcentrationRiskByTypeAxis_CustomerConcentrationRiskMember_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" unitRef="U003" decimals="0" scale="-2" format="ixt:fixed-zero">&#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>


</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'; font-size: 10pt;">We did <ix:nonFraction name="us-gaap:ContractWithCustomerLiability" id="Fact_b489fd8d13cd44ac881f88d0399e85ba" contextRef="c20230331_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" unitRef="U002" decimals="-6" scale="6" format="ixt-sec:numwordsen"><ix:nonFraction name="us-gaap:ContractWithCustomerLiability" id="Fact_7e036662dabb4d88b9c6f301390f1788" contextRef="c20221231_TypeOfArrangementAxis_GlaxoSmithKlineCollaborationMember" unitRef="U002" decimals="-6" scale="6" format="ixt-sec:numwordsen">no</ix:nonFraction></ix:nonFraction>t have any
    deferred revenue from our relationship with GSK at March 31, 2023 or December 31, 2022.</div>
</ix:continuation></div>

  <div><br />
  </div>

  <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
    <div class="BRPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">10</div>

    </div>

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

    <div class="BRPFPageHeader">
      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>
<div><ix:nonNumeric name="us-gaap:EarningsPerShareTextBlock" id="Text_e075129cfb9942b3964291d17e5f7c43" contextRef="c20230101to20230331" escape="true" continuedAt="Text_687a3c3820c94683ad197fa31a59e6571">
<div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">5. Basic and Diluted Net Loss Per Share</div>
</ix:nonNumeric>

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  <ix:continuation id="Text_687a3c3820c94683ad197fa31a59e6572" continuedAt="Text_687a3c3820c94683ad197fa31a59e6573"><ix:nonNumeric name="us-gaap:EarningsPerSharePolicyTextBlock" id="Text_9471c38bb7ae4e1287d0671ecea462a6" contextRef="c20230101to20230331" escape="true" continuedAt="Text_e15733be417c4daf9d9c6a1eb8d8f6b91">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Basic net loss per share</div>
</ix:nonNumeric></ix:continuation>
  <ix:continuation id="Text_687a3c3820c94683ad197fa31a59e6573" continuedAt="Text_687a3c3820c94683ad197fa31a59e6574"><ix:continuation id="Text_e15733be417c4daf9d9c6a1eb8d8f6b91" continuedAt="Text_e15733be417c4daf9d9c6a1eb8d8f6b92">
<div><br />
  </div>
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  <ix:continuation id="Text_687a3c3820c94683ad197fa31a59e6574" continuedAt="Text_687a3c3820c94683ad197fa31a59e6575"><ix:continuation id="Text_e15733be417c4daf9d9c6a1eb8d8f6b92" continuedAt="Text_e15733be417c4daf9d9c6a1eb8d8f6b93">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We calculated our basic net loss per share for the three months ended&#160;March 31, 2023 and 2022 by dividing our net loss by our weighted-average number of common shares outstanding during the period.</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_687a3c3820c94683ad197fa31a59e6575" continuedAt="Text_687a3c3820c94683ad197fa31a59e6576"><ix:continuation id="Text_e15733be417c4daf9d9c6a1eb8d8f6b93" continuedAt="Text_e15733be417c4daf9d9c6a1eb8d8f6b94">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_687a3c3820c94683ad197fa31a59e6576" continuedAt="Text_687a3c3820c94683ad197fa31a59e6577"><ix:continuation id="Text_e15733be417c4daf9d9c6a1eb8d8f6b94" continuedAt="Text_e15733be417c4daf9d9c6a1eb8d8f6b95">
<div style="display:none;"><br /></div>
<div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Diluted net loss per share</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_687a3c3820c94683ad197fa31a59e6577" continuedAt="Text_687a3c3820c94683ad197fa31a59e6578"><ix:continuation id="Text_e15733be417c4daf9d9c6a1eb8d8f6b95" continuedAt="Text_e15733be417c4daf9d9c6a1eb8d8f6b96">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_687a3c3820c94683ad197fa31a59e6578" continuedAt="Text_687a3c3820c94683ad197fa31a59e6579"><ix:continuation id="Text_e15733be417c4daf9d9c6a1eb8d8f6b96" continuedAt="Text_e15733be417c4daf9d9c6a1eb8d8f6b97">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">For the three months ended&#160;March 31, 2023 and 2022, 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 from the following would have had an anti-dilutive effect on net loss
    per share:</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_687a3c3820c94683ad197fa31a59e6579" continuedAt="Text_687a3c3820c94683ad197fa31a59e65710"><ix:continuation id="Text_e15733be417c4daf9d9c6a1eb8d8f6b97" continuedAt="Text_e15733be417c4daf9d9c6a1eb8d8f6b98">
<div><br />
  </div>
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  <tr>

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

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

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_8b907fce034b4f1badde44a8fb62a0b6" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_2b7cd2d9d34345fc9c896a1aa0b9ffed" contextRef="c20220331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">0</ix:nonFraction></ix:nonFraction> percent convertible senior notes, or <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_44599631b354431d83fbafd427b84a2e" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_0ea297d0210a42d9a665d5dda26140b2" contextRef="c20220331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">0</ix:nonFraction></ix:nonFraction>% Notes;</div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_687a3c3820c94683ad197fa31a59e65711" continuedAt="Text_687a3c3820c94683ad197fa31a59e65712"><ix:continuation id="Text_e15733be417c4daf9d9c6a1eb8d8f6b99" continuedAt="Text_e15733be417c4daf9d9c6a1eb8d8f6b910">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

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

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

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Note hedges related to the <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_cbe2bcc4c3d14b47bcbdeabac6ac057d" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_b7898ddbacfc4ae1946b18f1568fd7cf" contextRef="c20220331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">0</ix:nonFraction></ix:nonFraction>% Notes;</div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_687a3c3820c94683ad197fa31a59e65712" continuedAt="Text_687a3c3820c94683ad197fa31a59e65713"><ix:continuation id="Text_e15733be417c4daf9d9c6a1eb8d8f6b910" continuedAt="Text_e15733be417c4daf9d9c6a1eb8d8f6b911">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

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

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

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_e41939393b224ee783597306dc36daac" contextRef="c20220331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_c5e88dec0bd1430ca7e7d1de977b5a01" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal">0.125</ix:nonFraction></ix:nonFraction> percent convertible senior notes, or <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_a933b4f7afa1473d9df0d94a8d4afeb2" contextRef="c20220331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_5fde4c84acc044728945d893da112927" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal">0.125</ix:nonFraction></ix:nonFraction>% Notes;</div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_687a3c3820c94683ad197fa31a59e65713" continuedAt="Text_687a3c3820c94683ad197fa31a59e65714"><ix:continuation id="Text_e15733be417c4daf9d9c6a1eb8d8f6b911" continuedAt="Text_e15733be417c4daf9d9c6a1eb8d8f6b912">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

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

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

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Note hedges related to the <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_a93777dfde714e38820482b10cce8665" contextRef="c20220331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_2ace2f3096e942c4bf2967102938f98f" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal">0.125</ix:nonFraction></ix:nonFraction>% Notes;</div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_687a3c3820c94683ad197fa31a59e65714" continuedAt="Text_687a3c3820c94683ad197fa31a59e65715"><ix:continuation id="Text_e15733be417c4daf9d9c6a1eb8d8f6b912" continuedAt="Text_e15733be417c4daf9d9c6a1eb8d8f6b913">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

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

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

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Dilutive stock options;</div>
        </td>

  </tr>


</table>
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  <ix:continuation id="Text_687a3c3820c94683ad197fa31a59e65715" continuedAt="Text_687a3c3820c94683ad197fa31a59e65716"><ix:continuation id="Text_e15733be417c4daf9d9c6a1eb8d8f6b913" continuedAt="Text_e15733be417c4daf9d9c6a1eb8d8f6b914">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

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

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

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Unvested restricted stock units, or RSUs;</div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_687a3c3820c94683ad197fa31a59e65716" continuedAt="Text_687a3c3820c94683ad197fa31a59e65717"><ix:continuation id="Text_e15733be417c4daf9d9c6a1eb8d8f6b914" continuedAt="Text_e15733be417c4daf9d9c6a1eb8d8f6b915">
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  <tr>

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

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

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Unvested performance restricted stock units, or PRSUs; and</div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_687a3c3820c94683ad197fa31a59e65717" continuedAt="Text_687a3c3820c94683ad197fa31a59e65718"><ix:continuation id="Text_e15733be417c4daf9d9c6a1eb8d8f6b915" continuedAt="Text_e15733be417c4daf9d9c6a1eb8d8f6b916">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

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

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

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Employee Stock Purchase Plan, or ESPP.</div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_687a3c3820c94683ad197fa31a59e65718" continuedAt="Text_687a3c3820c94683ad197fa31a59e65719"><ix:continuation id="Text_e15733be417c4daf9d9c6a1eb8d8f6b916" continuedAt="Text_e15733be417c4daf9d9c6a1eb8d8f6b917">
<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'; font-size: 10pt;">Additionally as of March 31, 2023, we had
    warrants related to our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_79673f01eb3f4d0f8cc2a2ee82ba16a8" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">0</ix:nonFraction>% and <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_8b9684e867694bc788bcce48cf27b9cb" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal">0.125</ix:nonFraction>%
    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>
</ix:continuation></ix:continuation></div>

  <div><br />
  </div>
<div><ix:nonNumeric name="us-gaap:InvestmentTextBlock" id="Text_b6e1a67fcacc41d1be3b24f234df60ad" contextRef="c20230101to20230331" escape="true" continuedAt="Text_da36743d84b04122bdcc974850e94ba31">
<div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">6.&#160; Investments</div>
</ix:nonNumeric>

  <ix:continuation id="Text_da36743d84b04122bdcc974850e94ba31" continuedAt="Text_da36743d84b04122bdcc974850e94ba32">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_da36743d84b04122bdcc974850e94ba32" continuedAt="Text_da36743d84b04122bdcc974850e94ba33"><ix:nonNumeric name="us-gaap:InvestmentsClassifiedByContractualMaturityDateTableTextBlock" id="Text_88180c6e643a4b7eb3d2e8e8e7abb05a" contextRef="c20230101to20230331" escape="true" continuedAt="Text_be87bcd1a980409b9b5e60eae15f5e6c1">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">The following table summarizes the contract maturity of the available-for-sale securities we held as of March 31, 2023:</div>
</ix:nonNumeric></ix:continuation>
  <ix:continuation id="Text_da36743d84b04122bdcc974850e94ba33" continuedAt="Text_da36743d84b04122bdcc974850e94ba34"><ix:continuation id="Text_be87bcd1a980409b9b5e60eae15f5e6c1" continuedAt="Text_be87bcd1a980409b9b5e60eae15f5e6c2">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_da36743d84b04122bdcc974850e94ba34" continuedAt="Text_da36743d84b04122bdcc974850e94ba35"><ix:continuation id="Text_be87bcd1a980409b9b5e60eae15f5e6c2">
<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><span style="text-indent: 0pt;"><ix:nonNumeric name="ions:MaximumContractMaturityPeriodRange1" id="Fact_4b3282e6abbf4694b90d56a12cb3a78d" contextRef="c20230101to20230331" 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'; font-size: 10pt;"><ix:nonFraction name="ions:AvailableForSaleSecuritiesDebtMaturitiesWithinOneYearPercentage" id="Fact_26a36804df4340729bec0b2f463acda4" contextRef="c20230331" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">74</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'; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">After <span style="text-indent: 0pt;"><ix:nonNumeric name="ions:MaximumContractMaturityPeriodRange1" id="Fact_3bd993e525784a5398b297b7856fe228" contextRef="c20230101to20230331" format="ixt-sec:durwordsen">one year</ix:nonNumeric></span>
            but within <span style="text-indent: 0pt;"><ix:nonNumeric name="ions:MaximumContractMaturityPeriodRange2" id="Fact_beb1ea76eb4a4045aff26b90fc4a4ee3" contextRef="c20230101to20230331" format="ixt-sec:durwordsen">two years</ix:nonNumeric></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'; font-size: 10pt;"><ix:nonFraction name="ions:AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage" id="Fact_b3c2ee50dd694d208197df43360458a9" contextRef="c20230331" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">23</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'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">After <span style="text-indent: 0pt;"><ix:nonNumeric name="ions:MaximumContractMaturityPeriodRange2" id="Fact_812c571149d64b329fe4410606d76c7a" contextRef="c20230101to20230331" format="ixt-sec:durwordsen">two years</ix:nonNumeric></span>
            but within <span style="text-indent: 0pt;"><span style="-sec-ix-hidden:Fact_f12cc57cfa544d218ac6c26f9aae5797">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'; font-size: 10pt;"><ix:nonFraction name="ions:AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage" id="Fact_8cd01e7f5688446294ec6f1b2d7e38df" contextRef="c20230331" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">3</ix:nonFraction></div>
        </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'; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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">&#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'; font-size: 10pt;"><ix:nonFraction name="ions:AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage" id="Fact_6217a171f5784696968b178278e97ffa" contextRef="c20230331" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">100</ix:nonFraction></div>
        </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'; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_da36743d84b04122bdcc974850e94ba35" continuedAt="Text_da36743d84b04122bdcc974850e94ba36">
<div style="text-align: left; font-family: Calibri; font-size: 12pt;"><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'; font-size: 10pt;">As illustrated above, at March 31, 2023,
    <ix:nonFraction name="ions:AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage" id="Fact_ecfa1cb8a4484b48a192e8436b1431fe" contextRef="c20230331" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">97</ix:nonFraction> percent of our available-for-sale securities had a maturity of less than <ix:nonNumeric name="ions:MaximumContractMaturityPeriodRange2" id="Fact_34c87d75876e42c988ffebc06f56b6a3" contextRef="c20230101to20230331" format="ixt-sec:durwordsen">two years</ix:nonNumeric>.</div>
</ix:continuation>
  <ix:continuation id="Text_da36743d84b04122bdcc974850e94ba37" continuedAt="Text_da36743d84b04122bdcc974850e94ba38">
<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'; font-size: 10pt;">All of our available-for-sale debt 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>
  <ix:continuation id="Text_da36743d84b04122bdcc974850e94ba39" continuedAt="Text_da36743d84b04122bdcc974850e94ba310">
<div><br />
  </div>
</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'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">We invest in available-for-sale securities</span> with strong credit
    ratings and an investment grade rating at or above A-1, P-1 or F-1 by Standard &amp; Poor&#8217;s, Moody&#8217;s or Fitch, 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'; font-size: 10pt;">At March 31, 2023, we had
    an equity ownership interest of less than 20 percent in <ix:nonFraction name="ions:NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment" id="Fact_b7edbc55e46842cb916a4ced56279788" contextRef="c20230331" unitRef="U006" decimals="INF" scale="0" format="ixt-sec:numwordsen">seven</ix:nonFraction> private companies and <ix:nonFraction name="ions:NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment" id="Fact_8144a98eb4174391a5f3065f3f804da4" contextRef="c20230331" unitRef="U006" decimals="INF" scale="0" format="ixt-sec:numwordsen">three</ix:nonFraction> public companies with which we conduct business.</div>
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    <div class="BRPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">11</div>

    </div>

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

    <div class="BRPFPageHeader">
      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </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'; font-size: 10pt;">The following is a summary of our investments (in thousands):</div>
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  </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;" 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'; font-size: 10pt; font-weight: bold; text-indent: 6.5pt;">Amortized</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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;" 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'; 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; padding-bottom: 2px;" 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'; font-size: 10pt; font-weight: bold;">Cost</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 10pt; font-weight: bold;">Gains</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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">
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; 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>

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          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><span style="text-decoration: underline;">Available-for-sale debt securities:</span></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>

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    <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'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleAmortizedCostCurrent" id="Fact_7842515e18104a5cafcff84ddb01d951" contextRef="c20230331_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">623,940</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'; 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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxCurrent" id="Fact_c7e1b54bc6f94cda93f41712a4a9675c" contextRef="c20230331_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">62</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'; 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'; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent" id="Fact_6987932b0c734a95908cba3dde93f730" contextRef="c20230331_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">6,026</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'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecuritiesCurrent" id="Fact_35d357c29e5b420daf82588703d78d8d" contextRef="c20230331_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">617,976</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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleAmortizedCostCurrent" id="Fact_80e0d5c6be1c4870adc06685000bf257" contextRef="c20230331_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">247,629</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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxCurrent" id="Fact_18ba7ad7166c418da8278eb1c1894a6f" contextRef="c20230331_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">69</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'; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent" id="Fact_e9cc451da55c4d1c9aa3ad82c7ca9aae" contextRef="c20230331_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,283</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecuritiesCurrent" id="Fact_9e8a5c54173d453cb9fb728033354336" contextRef="c20230331_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">246,415</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleAmortizedCostCurrent" id="Fact_17f5c15fd8fe452b890ee866cfaa6b85" contextRef="c20230331_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">556,394</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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxCurrent" id="Fact_45e8bcb24cc241f2bf8f293a9b67a6a6" contextRef="c20230331_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">62</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'; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent" id="Fact_36dcce36e9b446bcb8f2877352fd5851" contextRef="c20230331_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">3,738</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecuritiesCurrent" id="Fact_cf007fb70961423eb9a3dd191872008b" contextRef="c20230331_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">552,718</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;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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;" 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleAmortizedCostCurrent" id="Fact_7c05793868aa4afb94fcfb88fcffcb2b" contextRef="c20230331_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">57,322</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 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">
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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>

  </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'; font-size: 10pt;">Total debt 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleAmortizedCostCurrent" id="Fact_3e165eb36915445a94e7bca3626be047" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,485,285</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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxCurrent" id="Fact_3c026731cf6c4d2c9f3bb6487eb52874" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">197</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'; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent" id="Fact_cbaf34a8cf1344ed8d1c9bd3764052c6" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">11,545</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecuritiesCurrent" id="Fact_401ef7ec0ee84b33b734c6646f73945d" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,473,937</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%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Corporate debt 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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleAmortizedCostNoncurrent" id="Fact_e739ce406a594fdab205b3f709378b35" contextRef="c20230331_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">200,661</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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent" id="Fact_1465e0f748cd4bfaa10d9f2bc25757c3" contextRef="c20230331_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">336</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'; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxNoncurrent" id="Fact_28d6823308c14eabb012545df1bbf47e" contextRef="c20230331_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">5,205</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecuritiesNoncurrent" id="Fact_dff0a77ea162428eac31903b7ae1af1c" contextRef="c20230331_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">195,792</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleAmortizedCostNoncurrent" id="Fact_4069992e62e44ec39ab5806e1ac879fa" contextRef="c20230331_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">99,635</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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent" id="Fact_13b8b3118986468c94cef784db3d7d85" contextRef="c20230331_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">256</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'; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxNoncurrent" id="Fact_8c034ba7ebd94e519637bf63e04e1b9f" contextRef="c20230331_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">649</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecuritiesNoncurrent" id="Fact_907c5df34a09413bb109221fad1ea266" contextRef="c20230331_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">99,242</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 52%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Debt securities issued by the U.S. Treasury</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleAmortizedCostNoncurrent" id="Fact_e43e28c5271b42a889a3b5a4967cc28d" contextRef="c20230331_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">257,651</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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent" id="Fact_4a47ab58cf674aa491198b0931ea7362" contextRef="c20230331_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">364</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'; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxNoncurrent" id="Fact_54bac431fed2433b9abbb4c98f4e8737" contextRef="c20230331_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">2,726</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecuritiesNoncurrent" id="Fact_df46987f0ff442a68229243874a3a796" contextRef="c20230331_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">255,289</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%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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: #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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleAmortizedCostNoncurrent" id="Fact_9945c8a3aa274e52aa7dfeabc6567ab4" contextRef="c20230331_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">14,564</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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent" id="Fact_2aa6d352ef954e92b94b3e1d7fb0194a" contextRef="c20230331_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">106</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'; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxNoncurrent" id="Fact_e6854048f6c941b08d43417760c49b8d" contextRef="c20230331_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">182</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecuritiesNoncurrent" id="Fact_d4953054b98b42dba9d5bed9a4393226" contextRef="c20230331_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">14,488</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;">
          <div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total debt securities with a maturity of more than one 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleAmortizedCostNoncurrent" id="Fact_2b2ee63d727e423482b317c18a37ce81" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">572,511</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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent" id="Fact_22456af2bd1a42a5aaa84149b3a6373e" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,062</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'; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxNoncurrent" id="Fact_3f93907b739e4f8a80f71070bbbc98e2" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">8,762</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecuritiesNoncurrent" id="Fact_33930b14001f46ccb9bf26b44f06a253" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">564,811</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: 52%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: 27pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total available-for-sale 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">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_c63efe923e13426992c34154ca0ceb66" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">2,057,796</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_4d9475d7048b443985ccf0e54c482dde" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,259</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'; 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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_abe680e773e045d898d7e780327a8001" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">20,307</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'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_ed64a9779a3842959199d38607dc68f6" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">2,038,748</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%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><span style="text-decoration: underline;">Equity securities:</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">&#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>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: 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: 52%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Publicly traded 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNiCost" id="Fact_795298199a7149089987fd608d910788" contextRef="c20230331_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">11,897</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'; 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'; font-size: 10pt;"><ix:nonFraction name="ions:EquitySecuritiesFvNiAccumulatedGrossUnrealizedGain" id="Fact_95a1e63d6d4c49f48092f55cc7344a6f" contextRef="c20230331_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; 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'; font-size: 10pt;">(<ix:nonFraction name="ions:EquitySecuritiesFvNiAccumulatedGrossUnrealizedLoss" id="Fact_720e14f204184668ac412128829c1d4c" contextRef="c20230331_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">4,508</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'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNi" id="Fact_c9668cdfca24444facba84f5586a8b21" contextRef="c20230331_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">7,389</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;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Privately held equity securities included in deposits and other assets (3)</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNiCost" id="Fact_642c9681829a411280b706605512aec4" contextRef="c20230331_FinancialInstrumentAxis_EquitySecuritiesPrivateCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">23,115</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'; font-size: 10pt;"><ix:nonFraction name="ions:EquitySecuritiesFvNiAccumulatedGrossUnrealizedGain" id="Fact_5465f26f407f4c8cbf1a7f4bc78d58bb" contextRef="c20230331_FinancialInstrumentAxis_EquitySecuritiesPrivateCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">25,001</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'; font-size: 10pt;">(<ix:nonFraction name="ions:EquitySecuritiesFvNiAccumulatedGrossUnrealizedLoss" id="Fact_8f26e7f4482346919fb9fd971a0e1bd2" contextRef="c20230331_FinancialInstrumentAxis_EquitySecuritiesPrivateCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">5,125</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNi" id="Fact_c86ece7c238c409db75f4e86d57eaa03" contextRef="c20230331_FinancialInstrumentAxis_EquitySecuritiesPrivateCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">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">&#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'; 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">&#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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNiCost" id="Fact_74700e6175be499286aad7c1da529560" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">35,012</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'; font-size: 10pt;"><ix:nonFraction name="ions:EquitySecuritiesFvNiAccumulatedGrossUnrealizedGain" id="Fact_023010caa8f343509b0246de63732628" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">25,001</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'; font-size: 10pt;">(<ix:nonFraction name="ions:EquitySecuritiesFvNiAccumulatedGrossUnrealizedLoss" id="Fact_b4350186c9724e47b1cac8c01c4216b9" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">9,633</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNi" id="Fact_10dc545d20404abda7146b5a706c0e00" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">50,380</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>

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    <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 4px;">
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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">
          <div style="color: #000000; font-family: 'Times New Roman'; 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;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiCost" id="Fact_6c45e37635ae4e82a8fe9a524ce7bc4f" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">2,092,808</ix:nonFraction></div>
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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'; 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;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedGain" id="Fact_5ab4e59a3fb946b2bfa63a42fd6cc9c5" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">26,260</ix:nonFraction></div>
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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'; 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;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss" id="Fact_571cea17cf8743fbb59b7749cbf08cd2" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">29,940</ix:nonFraction></div>
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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'; font-size: 10pt;">)</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">
          <div style="color: #000000; font-family: 'Times New Roman'; 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;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi" id="Fact_29d056dd0bc546a5b95f13a73db1588f" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">2,089,128</ix:nonFraction></div>
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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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    <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; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold; text-indent: 6.5pt;">Amortized</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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;" 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'; 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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          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"><span style="text-indent: 0pt;">December 31, 2022</span></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; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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;" 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'; font-size: 10pt; font-weight: bold;">Gains</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 10pt; font-weight: bold;">Losses</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 10pt; font-weight: bold;">Fair Value</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;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><span style="text-decoration: underline;">Available-for-sale debt securities:</span></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'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleAmortizedCostCurrent" id="Fact_b358568c049541b1856e64106205b629" contextRef="c20221231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">513,790</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'; 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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxCurrent" id="Fact_870aab605dd4403c879855738490612a" contextRef="c20221231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">23</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'; 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'; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent" id="Fact_e219351c2ba44027b99a7eb94f4fb4bd" contextRef="c20221231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">4,365</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecuritiesCurrent" id="Fact_baf860337cb14231b2612b277c5a61c8" contextRef="c20221231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">509,448</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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleAmortizedCostCurrent" id="Fact_68fdb285d5a54bedba4551932330f29f" contextRef="c20221231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">133,585</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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxCurrent" id="Fact_90dbffe642224d96bbf19226414d77d9" contextRef="c20221231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent" id="Fact_1777d6b10a6444f78df8d692409a590a" contextRef="c20221231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,829</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecuritiesCurrent" id="Fact_2130cf6d51914dc0afd1eccb0e4dfdad" contextRef="c20221231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">131,756</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleAmortizedCostCurrent" id="Fact_d8fc413c165c4a2c8aa4472257c08e29" contextRef="c20221231_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">512,655</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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxCurrent" id="Fact_c7bb5d4884cd42d0a8a8ff87cdcd691a" contextRef="c20221231_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">23</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'; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent" id="Fact_32a3a41f82bb44c799d99e85af07437d" contextRef="c20221231_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">5,124</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecuritiesCurrent" id="Fact_4ed162913c2d4a49b2bae214aa82a90e" contextRef="c20221231_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">507,554</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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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">
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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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecuritiesCurrent" id="Fact_072984a5e1e94320b84fd889d20ca860" contextRef="c20221231_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">56,816</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%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleAmortizedCostCurrent" id="Fact_1df79ce301a5455887127b0dbc862117" contextRef="c20221231_FinancialInstrumentAxis_OtherDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">6,008</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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxCurrent" id="Fact_9518b3aee686426f8779a9bf6acb315d" contextRef="c20221231_FinancialInstrumentAxis_OtherDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent" id="Fact_1814aeb1e427480f8c7ee6e199f663ac" contextRef="c20221231_FinancialInstrumentAxis_OtherDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">14</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecuritiesCurrent" id="Fact_f1f954b1e748471598a1eb7b37857cc0" contextRef="c20221231_FinancialInstrumentAxis_OtherDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">5,994</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;">
          <div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total debt securities with a maturity of one year or less</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleAmortizedCostCurrent" id="Fact_5d62eb1de663460d8a9d559d81878a58" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,223,522</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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxCurrent" id="Fact_32d0c20dd09a4965be6545f5ef1e1d0e" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">64</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'; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent" id="Fact_a65f661f76de418c8ded0d80f7684b50" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">12,018</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecuritiesCurrent" id="Fact_5269f1e3ba9b4b5f9397e201edccca32" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,211,568</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: 52%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleAmortizedCostNoncurrent" id="Fact_a2fd30f9900b415194cd94d357af784b" contextRef="c20221231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">227,631</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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent" id="Fact_34ab02ad304f441abe8a81962651c7ce" contextRef="c20221231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">14</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'; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxNoncurrent" id="Fact_3d4b4abb3a29485786b07cbc63b828cb" contextRef="c20221231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">10,143</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecuritiesNoncurrent" id="Fact_e00dab3b4cb04062a2e6a17f853d0e52" contextRef="c20221231_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">217,502</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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleAmortizedCostNoncurrent" id="Fact_d714f0d4eecc4d92b9b830449bba7fd1" contextRef="c20221231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">34,339</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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent" id="Fact_270ced43418a4c2faa9a7f0a3bd756eb" contextRef="c20221231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxNoncurrent" id="Fact_cc8c6fd4825a4a8ca13fdce32ea0a599" contextRef="c20221231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,040</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecuritiesNoncurrent" id="Fact_11b446490081470aa73bc2871b0b1042" contextRef="c20221231_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">33,299</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleAmortizedCostNoncurrent" id="Fact_e8d68ba6fad84cecafc9cdd32dea1e2f" contextRef="c20221231_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">245,030</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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent" id="Fact_28fa2a9aa6c3425bb5c7af4315f2d4c3" contextRef="c20221231_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxNoncurrent" id="Fact_feb5ebb376f64b648a49adafb20944f7" contextRef="c20221231_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">4,109</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecuritiesNoncurrent" id="Fact_5a7c49cad6044951b9d764adb62179ca" contextRef="c20221231_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">240,921</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;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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;" 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleAmortizedCostNoncurrent" id="Fact_b4ec0071c45247e3b27a4b280e593780" contextRef="c20221231_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">18,314</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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent" id="Fact_31520233cfb642e0bb7685bb15133f3a" contextRef="c20221231_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">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>

    <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'; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxNoncurrent" id="Fact_81b005a6831247d6a900198d8738b3d0" contextRef="c20221231_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">329</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecuritiesNoncurrent" id="Fact_e281a6848521414491c86fcd9f85c8a9" contextRef="c20221231_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">18,101</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: 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'; font-size: 10pt;">Total debt 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleAmortizedCostNoncurrent" id="Fact_d8f9bd55d10c46e8a7923b828bf66f7b" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">525,314</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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent" id="Fact_9edb30f88d124e4f98e5fc6733baa317" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">130</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'; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxNoncurrent" id="Fact_35b1772ea2884933bfa48eab5441097a" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">15,621</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecuritiesNoncurrent" id="Fact_bd78e79378ff4eecb24ada86ee7d4685" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">509,823</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;">
          <div style="text-align: left; text-indent: 27pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total available-for-sale debt securities</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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAmortizedCostBasis" id="Fact_d8842e093daf4aa8a441e191da86ea99" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,748,836</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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" id="Fact_4a16a27e0c4144fea9d33948c111d40b" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">194</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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" id="Fact_5d60bf6074c241728013af9aebe4f553" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">27,639</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'; 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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_282a1da5440143508a579978a45d2601" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,721,391</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: 52%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><span style="text-decoration: underline;">Equity securities:</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">&#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%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Publicly traded equity securities included in other current assets (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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNiCost" id="Fact_b8a712e5f4af42cdb9018ff5937f5e79" contextRef="c20221231_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">11,897</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'; 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'; font-size: 10pt;"><ix:nonFraction name="ions:EquitySecuritiesFvNiAccumulatedGrossUnrealizedGain" id="Fact_8b35758c336d4c378e03fdeaeaa046d7" contextRef="c20221231_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; 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'; font-size: 10pt;">(<ix:nonFraction name="ions:EquitySecuritiesFvNiAccumulatedGrossUnrealizedLoss" id="Fact_d23a46f787e04e259237398f99054fea" contextRef="c20221231_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,358</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'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNi" id="Fact_8651c4c7cf0b40ec9603b79cfd50d43b" contextRef="c20221231_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">10,539</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%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Privately held 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNiCost" id="Fact_2faff3973c0f4ab0bd4fcffd3307bce8" contextRef="c20221231_FinancialInstrumentAxis_EquitySecuritiesPrivateCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">23,115</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'; font-size: 10pt;"><ix:nonFraction name="ions:EquitySecuritiesFvNiAccumulatedGrossUnrealizedGain" id="Fact_e3dee8ea479d4e8fbda5e68ba7814a7e" contextRef="c20221231_FinancialInstrumentAxis_EquitySecuritiesPrivateCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">17,257</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'; font-size: 10pt;"><ix:nonFraction name="ions:EquitySecuritiesFvNiAccumulatedGrossUnrealizedLoss" id="Fact_53a829bbd230481e83c9e355f575a8b7" contextRef="c20221231_FinancialInstrumentAxis_EquitySecuritiesPrivateCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNi" id="Fact_90b3f028c4c64df180eb902de39038aa" contextRef="c20221231_FinancialInstrumentAxis_EquitySecuritiesPrivateCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">40,372</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;">
          <div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total equity securities</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNiCost" id="Fact_cfbea931b88e4baf9112a7e54d02cbfc" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">35,012</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'; font-size: 10pt;"><ix:nonFraction name="ions:EquitySecuritiesFvNiAccumulatedGrossUnrealizedGain" id="Fact_5e7e8a83411f4b40bf00d16a3e60d487" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">17,257</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'; font-size: 10pt;">(<ix:nonFraction name="ions:EquitySecuritiesFvNiAccumulatedGrossUnrealizedLoss" id="Fact_d45ad7a12cac403ea2d5a2edb37a0eed" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,358</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNi" id="Fact_8bd47c89fd1645cfa78adda562a9364e" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">50,911</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: 52%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: 27pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total available-for-sale debt 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'; 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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiCost" id="Fact_6808aa03681547cca1d6c98d32aab031" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,783,848</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'; 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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedGain" id="Fact_f7a5c21d883b40c784a842b4eab86b9d" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">17,451</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'; 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'; font-size: 10pt;">(<ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss" id="Fact_bf106be9d5824af3aa9e4c635557fb8a" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">28,997</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'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNi" id="Fact_ecad1868d9ae4c4cb68ebd3c78a85d30" contextRef="c20221231" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,772,302</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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  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:footnote id="Foot_2ec4116852e041e3a2a38cb16ff4ea22" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US">Includes investments classified as cash
            equivalents in our condensed consolidated balance sheets.</ix:footnote></div>
        </td>

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</table>
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    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(2)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:footnote id="Foot_20cf8a92586d4d88bc45b040cb662025" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US">Our publicly traded equity securities are
            included in other current assets. We recognize publicly traded equity securities at fair value. In the three months ended&#160;March 31, 2023, we recognized a $<ix:nonFraction name="us-gaap:EquitySecuritiesFvNiUnrealizedLoss" id="Fact_3313864190a543a6b47d32b6b504a1c9" contextRef="c20230101to20230331_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">3.2</ix:nonFraction>
            million unrealized loss in our condensed consolidated statements of operations related to a decrease in the fair value of our investments in publicly traded companies.</ix:footnote></div>
        </td>

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    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(3)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;"><ix:footnote id="Foot_55aad856d839435daad2d772a2ea1bc5" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">Our privately held equity securities are included in deposits and other assets. We recognize our privately held 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, which are Level 3 inputs<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">. In the three months ended March 31, 2023, we recorded a
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              consolidated statements of operations related to changes in the fair value of our investments in privately held companies.</span></ix:footnote></div>
        </td>

  </tr>


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  <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
    <div class="BRPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">12</div>

    </div>

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

    <div class="BRPFPageHeader">
      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </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'; font-size: 10pt;">The following is a summary of our investments we consider to be temporarily impaired at March 31, 2023 (in thousands, except for number of investments):</div>
</ix:nonNumeric></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;" colspan="1">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; white-space: nowrap;" colspan="2">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Less than 12 Months of</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Temporary Impairment</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">More than 12 Months of</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Temporary Impairment</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Total Temporary</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Impairment</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; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Number of</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Investments</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 10pt; font-weight: bold;">Estimated</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Fair Value</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 10pt; font-weight: bold;">Unrealized</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Losses</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 10pt; font-weight: bold;">Estimated</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Fair Value</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 10pt; font-weight: bold;">Unrealized</div>
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    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; 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;" 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'; font-size: 10pt; font-weight: bold;">Unrealized</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Losses</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: 16%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Corporate debt securities</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsNumberOfPositions" id="Fact_333cdd7221c74a659058428cb96f027e" contextRef="c20230331_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U007" decimals="0" scale="0" format="ixt:num-dot-decimal">361</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12Months" id="Fact_2e0cac4f3e6445e4af1d421cd8ba2264" contextRef="c20230331_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">434,500</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>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; 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'; 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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss" id="Fact_903a58d3bf3c421b9166ac1d0a37f22d" contextRef="c20230331_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,697</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLonger" id="Fact_183b7171ce6948fe93c1afb5708dc040" contextRef="c20230331_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">291,713</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'; 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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLongerAccumulatedLoss" id="Fact_2bc4f2d4d6bd455e9474ce6348458023" contextRef="c20230331_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">9,534</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'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleUnrealizedLossPosition" id="Fact_39ca68f5ced34e02a3fb7f209ed77346" contextRef="c20230331_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">726,213</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'; 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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleUnrealizedLossPositionAccumulatedLoss" id="Fact_6a521c4aea4b4d6186a40cc4ac11ef16" contextRef="c20230331_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">11,231</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'; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 16%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsNumberOfPositions" id="Fact_f82ef35b85bc4b76a2ca3ea408acca74" contextRef="c20230331_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U007" decimals="0" scale="0" format="ixt:num-dot-decimal">68</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12Months" id="Fact_0a9f0760b76943a0bb457df5aa11d275" contextRef="c20230331_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">138,211</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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss" id="Fact_a606df5dbef24526ade176d96aa0c07b" contextRef="c20230331_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">424</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLonger" id="Fact_2d0505e6d78b437083a13a36af9d0e35" contextRef="c20230331_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">70,965</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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLongerAccumulatedLoss" id="Fact_be6630f1d422413eb69c31e0abbb4c84" contextRef="c20230331_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,508</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleUnrealizedLossPosition" id="Fact_9e4b0d43d3f14d11b3cdc492ef07dd02" contextRef="c20230331_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">209,176</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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleUnrealizedLossPositionAccumulatedLoss" id="Fact_eba3f72c498e466687adcba61f086b48" contextRef="c20230331_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,932</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'; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 16%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsNumberOfPositions" id="Fact_2e46b5062fb3478c908336d6d2d994c6" contextRef="c20230331_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U007" decimals="0" scale="0" format="ixt:num-dot-decimal">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">&#160;</td>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12Months" id="Fact_392a47ad8b314b019fde0f086884f91a" contextRef="c20230331_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">603,444</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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss" id="Fact_b473b5a2bf6f472895d5dbf195a86994" contextRef="c20230331_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">3,873</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLonger" id="Fact_631f14e2221f4205b5b6af1f14754c3c" contextRef="c20230331_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">91,448</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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLongerAccumulatedLoss" id="Fact_366adc85dd3e4261abd0ad4c81e9ed06" contextRef="c20230331_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">2,591</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleUnrealizedLossPosition" id="Fact_8fe8a8c8d9ba4dbe9a0815a2dd6c7215" contextRef="c20230331_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">694,892</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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleUnrealizedLossPositionAccumulatedLoss" id="Fact_039c758638b24f77831d5dfe6f4ab76e" contextRef="c20230331_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">6,464</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 16%; 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>

    <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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLonger" id="Fact_1ee53f584ab24cb6b581f7eae1eba196" contextRef="c20230331_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">32,792</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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLongerAccumulatedLoss" id="Fact_98453b0c0b144bba86ec994206fdc1cb" contextRef="c20230331_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">540</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleUnrealizedLossPosition" id="Fact_4d01726992bb4d94b31e50877ad828f0" contextRef="c20230331_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">55,570</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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleUnrealizedLossPositionAccumulatedLoss" id="Fact_401d55f983434e8d9399ad8c2fc7758d" contextRef="c20230331_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">680</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'; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: bottom; width: 16%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total temporarily impaired 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">&#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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsNumberOfPositions" id="Fact_7e1f0b8e65b4437a89df6913266edd37" contextRef="c20230331" unitRef="U007" decimals="0" scale="0" format="ixt:num-dot-decimal">603</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12Months" id="Fact_a321ec73c6744478ab33de1911123ebf" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,198,933</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'; 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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss" id="Fact_32652639154d4153a0f3bf2d89e86160" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">6,134</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'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLonger" id="Fact_c18b9c577f3c4038843a9b7ee496d0d4" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">486,918</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'; 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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLongerAccumulatedLoss" id="Fact_b3760c7e65ef40e2ab47903dd7c9443a" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">14,173</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'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleUnrealizedLossPosition" id="Fact_08acbc6cc04049ed9b3d48be01027292" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,685,851</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'; 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'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DebtSecuritiesAvailableForSaleUnrealizedLossPositionAccumulatedLoss" id="Fact_cf642061255f4432b68bd3618eb2a416" contextRef="c20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">20,307</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'; font-size: 10pt;">)</div>
        </td>

  </tr>


</table>
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  <ix:continuation id="Text_da36743d84b04122bdcc974850e94ba329" continuedAt="Text_da36743d84b04122bdcc974850e94ba330">
<div style="text-align: left; font-family: Calibri; font-size: 12pt;"><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_da36743d84b04122bdcc974850e94ba330">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">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
    rather than underlying credit deterioration for any of the issuers. We believe it is more likely than not that we will be able to hold our debt securities with declines in value to maturity. Therefore, we anticipate full recovery of our debt
    securities&#8217; amortized cost basis at maturity.</div>
</ix:continuation></div>

  <div style="text-align: left; font-family: Calibri; font-size: 12pt;"><br />
  </div>
<div><ix:nonNumeric name="us-gaap:FairValueDisclosuresTextBlock" id="Text_2a6de6f9bc2e421d838e9ff6c089fad5" contextRef="c20230101to20230331" escape="true" continuedAt="Text_bb15bb3b2914412eb6492f6a425264bc1">
<div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">7.&#160; Fair Value Measurements</div>
</ix:nonNumeric>

  <ix:continuation id="Text_bb15bb3b2914412eb6492f6a425264bc1" continuedAt="Text_bb15bb3b2914412eb6492f6a425264bc2">
<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'; font-size: 10pt;">The following tables present the major security types we held at March 31, 2023 and December 31, 2022 that we regularly measure and
    carry at fair value. 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 security&#8217;s fair value (in thousands):</div>
</ix:nonNumeric></ix:continuation>
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<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_bb15bb3b2914412eb6492f6a425264bc4" continuedAt="Text_bb15bb3b2914412eb6492f6a425264bc5"><ix:continuation id="Text_5aaf666acfd64ef4a0a55712c4daf5e42" continuedAt="Text_5aaf666acfd64ef4a0a55712c4daf5e43">
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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; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">At</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 31, 2023</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 10pt; font-weight: bold;">Quoted Prices in</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Active Markets</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">(Level 1)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 10pt; font-weight: bold;">Significant Other</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Observable Inputs</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">(Level 2)</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'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashAndCashEquivalentsFairValueDisclosure" id="Fact_ab8b93d31763462f825afbb8d94ca1c5" contextRef="c20230331_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">276,352</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">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashAndCashEquivalentsFairValueDisclosure" id="Fact_435272b4ab6d4fb0a17848af08d9ea64" contextRef="c20230331_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">276,352</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">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashAndCashEquivalentsFairValueDisclosure" id="Fact_b9e898ee93984d899874de0b216f6350" contextRef="c20230331_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_1b769ef466ea447fba9ad51918866940" contextRef="c20230331_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">813,768</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_1a622d10285342d4ab574fbc330e9b6a" contextRef="c20230331_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_2a11d5be65ff43b2bc3316d459599b2f" contextRef="c20230331_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">813,768</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-right: 6pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_4ce9866198094ab9bb0fba527e9f7a46" contextRef="c20230331_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">345,657</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>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_cc73c7dd4336416d8872098ddc72f3db" contextRef="c20230331_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_418e9f44ebbb42dd9a510d3d5c448b72" contextRef="c20230331_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">345,657</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: 64%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_144b8361be90457089523a487891e260" contextRef="c20230331_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">808,007</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_80cb88c905824e2f9a4af8d421a3ae6c" contextRef="c20230331_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">808,007</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_2e48b747b93e49a19ff9c8c29a110e0c" contextRef="c20230331_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_c11eb07ea3324e24902d31be146e2aba" contextRef="c20230331_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">71,316</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_5239338c06b14e6a85429a23967f6b00" contextRef="c20230331_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_d3641150e44941fa942aa4dc4b80dcba" contextRef="c20230331_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">71,316</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>
            <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Publicly traded equity securities included in other current assets (4)</div>
          </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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNi" id="Fact_345ac2114958402e8c0526123b413533" contextRef="c20230331_BalanceSheetLocationAxis_OtherCurrentAssetsMember_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">7,389</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNi" id="Fact_49579a46ef144e9db6adc23b832e2254" contextRef="c20230331_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">7,389</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNi" id="Fact_714e6b6bc417487db0580f5a9df0b246" contextRef="c20230331_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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: 4px; background-color: #CCEEFF;">
          <div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AssetsFairValueDisclosure" id="Fact_9623b6fc811d446d8de6fe8c0a84d07a" contextRef="c20230331_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">2,322,489</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AssetsFairValueDisclosure" id="Fact_5e3adc88dc374a21be5199cc974a06ca" contextRef="c20230331_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,091,748</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AssetsFairValueDisclosure" id="Fact_fb2ce086644c437499ac32ea8b2ab24d" contextRef="c20230331_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,230,741</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 class="BRPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">13</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 style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>
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<div><br />
  </div>
</ix:continuation></ix:continuation>

  <ix:continuation id="Text_bb15bb3b2914412eb6492f6a425264bc6" continuedAt="Text_bb15bb3b2914412eb6492f6a425264bc7"><ix:continuation id="Text_5aaf666acfd64ef4a0a55712c4daf5e44" continuedAt="Text_5aaf666acfd64ef4a0a55712c4daf5e45">
<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">At</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">December 31, 2022</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 10pt; font-weight: bold;">Quoted Prices in</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Active Markets</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">(Level 1)</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 10pt; font-weight: bold;">Significant Other</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Observable Inputs</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">(Level 2)</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'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashAndCashEquivalentsFairValueDisclosure" id="Fact_3abef904d1ac4dac9365cd6a89ce306b" contextRef="c20221231_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">211,655</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashAndCashEquivalentsFairValueDisclosure" id="Fact_d7eb290d8c5b4341953ea8ce19b70167" contextRef="c20221231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">211,655</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:CashAndCashEquivalentsFairValueDisclosure" id="Fact_9d277c8fc4ff4a19a7ee29dcea9663b9" contextRef="c20221231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_6d98cfd31fed4be1bc5dd4e5765ff970" contextRef="c20221231_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">726,950</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_880b4c0e0d2d48df987d8eb4b3893eda" contextRef="c20221231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_641d49c2d0c64af9adad977b14b03585" contextRef="c20221231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">726,950</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-right: 6pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_a02ee28d048e4f4a86d13e676be48142" contextRef="c20221231_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">165,055</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_2c0dd2ce365841a7940c2b161ab7aa5b" contextRef="c20221231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_276eb2ce23b74c76b7109fee3b729859" contextRef="c20221231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USGovernmentAgenciesDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">165,055</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_92f2c745baa2467ebc8da9f308582732" contextRef="c20221231_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">748,475</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_4f65ddc8bb1f41b18f4a4fafb05aa5bf" contextRef="c20221231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">748,475</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_cad6d847f28b41d1ba345ee379c53c3a" contextRef="c20221231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USTreasurySecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_8ac6126992144e2d902abafe0f05aaf1" contextRef="c20221231_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">74,917</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_c4b11390dafb4d68ab357a12be102e2b" contextRef="c20221231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_984ae9d0003e4112b370b64ac08e73fa" contextRef="c20221231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">74,917</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: left; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_3884240483e242908ec151549d8a9266" contextRef="c20221231_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_OtherDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">5,994</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_a95b8a716a024353bd232c9287cc39cc" contextRef="c20221231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_OtherDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_bee8ae5848674561afc84c3a3eeddfb7" contextRef="c20221231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_OtherDebtSecuritiesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">5,994</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: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Publicly traded equity securities included in other current assets (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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNi" id="Fact_2d42bf872f544c81919721ce64a97544" contextRef="c20221231_BalanceSheetLocationAxis_OtherCurrentAssetsMember_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">10,539</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNi" id="Fact_e4b5ecb96353409f8174273ca47cf4bd" contextRef="c20221231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">10,539</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:EquitySecuritiesFvNi" id="Fact_a7b2fd7148674fabb6e271a364c858e7" contextRef="c20221231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_EquitySecuritiesPubliclyTradedCompaniesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:fixed-zero">&#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'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AssetsFairValueDisclosure" id="Fact_d3bd323a8b614ca5970873ceac15876b" contextRef="c20221231_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">1,943,585</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AssetsFairValueDisclosure" id="Fact_309c74f6dec14486a89fc6b78983b26a" contextRef="c20221231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel1Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">970,669</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AssetsFairValueDisclosure" id="Fact_11ff54c661534a3abddbec83ad68c19a" contextRef="c20221231_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">972,916</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_bb15bb3b2914412eb6492f6a425264bc7" continuedAt="Text_bb15bb3b2914412eb6492f6a425264bc8"><ix:continuation id="Text_5aaf666acfd64ef4a0a55712c4daf5e45" continuedAt="Text_5aaf666acfd64ef4a0a55712c4daf5e46">
<div><br />
  </div>
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  <ix:continuation id="Text_bb15bb3b2914412eb6492f6a425264bc8" continuedAt="Text_bb15bb3b2914412eb6492f6a425264bc9"><ix:continuation id="Text_5aaf666acfd64ef4a0a55712c4daf5e46" continuedAt="Text_5aaf666acfd64ef4a0a55712c4daf5e47">
<div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">The following footnotes reference lines in our condensed consolidated balance sheets:</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_bb15bb3b2914412eb6492f6a425264bc9" continuedAt="Text_bb15bb3b2914412eb6492f6a425264bc10"><ix:continuation id="Text_5aaf666acfd64ef4a0a55712c4daf5e47" continuedAt="Text_5aaf666acfd64ef4a0a55712c4daf5e48">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_bb15bb3b2914412eb6492f6a425264bc10" continuedAt="Text_bb15bb3b2914412eb6492f6a425264bc11"><ix:continuation id="Text_5aaf666acfd64ef4a0a55712c4daf5e48" continuedAt="Text_5aaf666acfd64ef4a0a55712c4daf5e49">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:footnote id="Foot_a07f61350d6c43dcbc95f9a5735b974a" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US">Included in cash and cash equivalents in our
            condensed consolidated balance sheets.</ix:footnote></div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_bb15bb3b2914412eb6492f6a425264bc11" continuedAt="Text_bb15bb3b2914412eb6492f6a425264bc12"><ix:continuation id="Text_5aaf666acfd64ef4a0a55712c4daf5e49" continuedAt="Text_5aaf666acfd64ef4a0a55712c4daf5e410">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_bb15bb3b2914412eb6492f6a425264bc12" continuedAt="Text_bb15bb3b2914412eb6492f6a425264bc13"><ix:continuation id="Text_5aaf666acfd64ef4a0a55712c4daf5e410" continuedAt="Text_5aaf666acfd64ef4a0a55712c4daf5e411">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(2)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:footnote id="Foot_67f6ff09f4d443248a7bd7fe03ce1bd9" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US">Included in short-term investments in our
            condensed consolidated balance sheets.</ix:footnote></div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_bb15bb3b2914412eb6492f6a425264bc13" continuedAt="Text_bb15bb3b2914412eb6492f6a425264bc14"><ix:continuation id="Text_5aaf666acfd64ef4a0a55712c4daf5e411" continuedAt="Text_5aaf666acfd64ef4a0a55712c4daf5e412">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_bb15bb3b2914412eb6492f6a425264bc14" continuedAt="Text_bb15bb3b2914412eb6492f6a425264bc15"><ix:continuation id="Text_5aaf666acfd64ef4a0a55712c4daf5e412" continuedAt="Text_5aaf666acfd64ef4a0a55712c4daf5e413">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(3)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:footnote id="Foot_2009e9e101cd4940acd892bb1ca9a15f" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US">$<ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_29824ec83f13463cb421396ade5c8f28" contextRef="c20230331_BalanceSheetLocationAxis_CashAndCashEquivalentsMember_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_USStatesAndPoliticalSubdivisionsMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">1.0</ix:nonFraction> million was included in cash and cash equivalents in our condensed consolidated balance sheets, with the difference included in short-term investments in our condensed
            consolidated balance sheets.</ix:footnote></div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_bb15bb3b2914412eb6492f6a425264bc15" continuedAt="Text_bb15bb3b2914412eb6492f6a425264bc16"><ix:continuation id="Text_5aaf666acfd64ef4a0a55712c4daf5e413" continuedAt="Text_5aaf666acfd64ef4a0a55712c4daf5e414">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_bb15bb3b2914412eb6492f6a425264bc16" continuedAt="Text_bb15bb3b2914412eb6492f6a425264bc17"><ix:continuation id="Text_5aaf666acfd64ef4a0a55712c4daf5e414" continuedAt="Text_5aaf666acfd64ef4a0a55712c4daf5e415">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(4)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:footnote id="Foot_fa6fd00113af47ccbbac20179fb575e4" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US">Included in other current assets in our
            condensed consolidated balance sheets.</ix:footnote></div>
        </td>

  </tr>


</table>
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  <ix:continuation id="Text_bb15bb3b2914412eb6492f6a425264bc17" continuedAt="Text_bb15bb3b2914412eb6492f6a425264bc18"><ix:continuation id="Text_5aaf666acfd64ef4a0a55712c4daf5e415" continuedAt="Text_5aaf666acfd64ef4a0a55712c4daf5e416">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_bb15bb3b2914412eb6492f6a425264bc18" continuedAt="Text_bb15bb3b2914412eb6492f6a425264bc19"><ix:continuation id="Text_5aaf666acfd64ef4a0a55712c4daf5e416">
<table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(5)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:footnote id="Foot_f2b545f45c3b4fac8bc6e5fc28fe7929" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US">$<ix:nonFraction name="us-gaap:AvailableForSaleSecuritiesDebtSecurities" id="Fact_a08692d747714e4f965095878b94278d" contextRef="c20221231_BalanceSheetLocationAxis_CashAndCashEquivalentsMember_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember_FinancialInstrumentAxis_CorporateDebtSecuritiesMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">11.0</ix:nonFraction> million was included in cash and cash equivalents in our condensed consolidated balance sheets, with the difference included in short-term investments in our condensed
            consolidated balance sheets.</ix:footnote></div>
        </td>

  </tr>


</table>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_bb15bb3b2914412eb6492f6a425264bc19" continuedAt="Text_bb15bb3b2914412eb6492f6a425264bc20">
<div style="text-align: left; font-family: Calibri; font-size: 12pt;"><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_bb15bb3b2914412eb6492f6a425264bc20" continuedAt="Text_bb15bb3b2914412eb6492f6a425264bc21">
<div style="text-align: left; margin-left: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;">Convertible Notes</div>
</ix:continuation>
  <ix:continuation id="Text_bb15bb3b2914412eb6492f6a425264bc21" continuedAt="Text_bb15bb3b2914412eb6492f6a425264bc22">
<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_bb15bb3b2914412eb6492f6a425264bc22">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_dfc304a4577d4a8b8ccf97e7be8f9791" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal">0.125</ix:nonFraction>% Notes and <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_b605dc05faaa4ecf92f3388ccd8e6140" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">0</ix:nonFraction>% Notes had a fair value of $<ix:nonFraction name="us-gaap:NotesPayableFairValueDisclosure" id="Fact_886896b6a5b643a387fb328dcc366ca9" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">506.3</ix:nonFraction> million and $<ix:nonFraction name="us-gaap:NotesPayableFairValueDisclosure" id="Fact_e2d5869342504cbea6cdb10162937afd" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">578.4</ix:nonFraction> million at March 31, 2023, respectively.
    Our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_450d1e85bcde4d249c30a51b40485724" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal">0.125</ix:nonFraction>% Notes and <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_841f4e4179944ccdbc5dc537cbfe62fe" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">0</ix:nonFraction>% Notes had a
    fair value of $<ix:nonFraction name="us-gaap:NotesPayableFairValueDisclosure" id="Fact_8ae98335d6764a84a41f7a8b186c6d75" contextRef="c20221231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">498.9</ix:nonFraction> million and $<ix:nonFraction name="us-gaap:NotesPayableFairValueDisclosure" id="Fact_572d2a1ef8f740a6958da9503d2f0642" contextRef="c20221231_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember_FairValueByFairValueHierarchyLevelAxis_FairValueInputsLevel2Member_FairValueByMeasurementFrequencyAxis_FairValueMeasurementsRecurringMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">587.3</ix:nonFraction>
    million at December 31, 2022, 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></div>

  <div><br />
  </div>
<div><ix:nonNumeric name="us-gaap:DisclosureOfCompensationRelatedCostsShareBasedPaymentsTextBlock" id="Text_95a42e74ad3448d4bcb3f3914e8d6dfe" contextRef="c20230101to20230331" escape="true" continuedAt="Text_8b6a4931d32c4ab3975dbfab9a804c981">
<div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">8. Stock-based Compensation Expense</div>
</ix:nonNumeric>

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<div><br />
  </div>
</ix:continuation>
  <ix:continuation id="Text_8b6a4931d32c4ab3975dbfab9a804c982" continuedAt="Text_8b6a4931d32c4ab3975dbfab9a804c983"><ix:nonNumeric name="us-gaap:ShareBasedCompensationOptionAndIncentivePlansPolicy" id="Text_c5ce94c54d424a5d9c24152ec62f851f" contextRef="c20230101to20230331" escape="true" continuedAt="Text_7b6ac5b603ee4195ac92b2b165195fca1">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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 condensed 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>
</ix:nonNumeric></ix:continuation>
  <ix:continuation id="Text_8b6a4931d32c4ab3975dbfab9a804c983" continuedAt="Text_8b6a4931d32c4ab3975dbfab9a804c984"><ix:continuation id="Text_7b6ac5b603ee4195ac92b2b165195fca1" continuedAt="Text_7b6ac5b603ee4195ac92b2b165195fca2">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_8b6a4931d32c4ab3975dbfab9a804c984" continuedAt="Text_8b6a4931d32c4ab3975dbfab9a804c985"><ix:continuation id="Text_7b6ac5b603ee4195ac92b2b165195fca2" continuedAt="Text_7b6ac5b603ee4195ac92b2b165195fca3">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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.</div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_8b6a4931d32c4ab3975dbfab9a804c985" continuedAt="Text_8b6a4931d32c4ab3975dbfab9a804c986"><ix:continuation id="Text_7b6ac5b603ee4195ac92b2b165195fca3" continuedAt="Text_7b6ac5b603ee4195ac92b2b165195fca4">
<div><br />
  </div>
</ix:continuation></ix:continuation>
  <ix:continuation id="Text_8b6a4931d32c4ab3975dbfab9a804c986" continuedAt="Text_8b6a4931d32c4ab3975dbfab9a804c987"><ix:continuation id="Text_7b6ac5b603ee4195ac92b2b165195fca4">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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>
</ix:continuation></ix:continuation>
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<div><br />
  </div>
</ix:continuation></div>

  <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
    <div class="BRPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">14</div>

    </div>

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

    <div class="BRPFPageHeader">
      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">For the three months ended&#160;March 31, 2023 and 2022, we used the
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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'; font-size: 10pt; font-style: italic;">Employee 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; white-space: nowrap;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">2023</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 10pt; font-weight: bold;">2022</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: 76%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Risk-free interest 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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          <div style="color: #000000; font-family: 'Times New Roman'; 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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">%</div>
        </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'; 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>

    <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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate" id="Fact_6fd1d504e21a42f18d1513595b6d94a7" contextRef="c20220101to20220331_AwardTypeAxis_EmployeeStockOptionMember_GranteeStatusAxis_ShareBasedPaymentArrangementEmployeeMember" unitRef="U003" decimals="3" scale="-2" format="ixt:num-dot-decimal">0.0</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'; font-size: 10pt;">%</div>
        </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'; 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'; 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'; font-size: 10pt;">%</div>
        </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'; 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>

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</table>
</ix:continuation></ix:continuation>
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    <td style="width: 18pt; vertical-align: top; font-family: 'Times New Roman'; font-size: 10pt;">*</td>

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          <div style="font-family: 'Times New Roman'; font-size: 10pt;"><ix:footnote id="Foot_74bbbb57209c4f53960b9d7c3438ee6b" footnoteRole="http://www.xbrl.org/2003/role/footnote" xml:lang="en-US">In 2021, our Compensation Committee approved
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            expected life of stock options granted to employees in the three months ended&#160;March 31, 2023 and 2022. Under the simplified method, we calculate the expected term as the average of the time-to-vesting and the contractual life of the options. As we gain additional
            historical information, we will transition to calculating our expected term based on our historical exercise patterns.</ix:footnote>&#160;</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'; font-size: 10pt; font-style: italic;">ESPP:</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; white-space: nowrap;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">2023</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 10pt; font-weight: bold;">2022</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'; font-size: 10pt;">Risk-free interest 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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRate" id="Fact_77dd56e1caba4fc6aea5e9e6e638ae5c" contextRef="c20230101to20230331_AwardTypeAxis_EmployeeStockMember" unitRef="U003" decimals="3" scale="-2" format="ixt:num-dot-decimal">5.2</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">%</div>
        </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'; 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>

    <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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate" id="Fact_c44f5d5a2f164df58a55c39c846c87a6" contextRef="c20220101to20220331_AwardTypeAxis_EmployeeStockMember" unitRef="U003" decimals="3" scale="-2" format="ixt:num-dot-decimal">0.0</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'; font-size: 10pt;">%</div>
        </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'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsWeightedAverageVolatilityRate" id="Fact_b5d4da261dad4007b283535f0efbd4b2" contextRef="c20220101to20220331_AwardTypeAxis_EmployeeStockMember" unitRef="U003" decimals="3" scale="-2" format="ixt:num-dot-decimal">50.2</ix:nonFraction></div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" colspan="1">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">%</div>
        </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'; 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">
          <div style="text-align: right; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:nonNumeric name="us-gaap:SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1" id="Fact_4cc29778c0e447968d90cd4b1be3691e" contextRef="c20230101to20230331_AwardTypeAxis_EmployeeStockMember" format="ixt-sec:durmonth">6</ix:nonNumeric> months</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: right; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><ix:nonNumeric name="us-gaap:SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1" id="Fact_6e6a732476bd479cad0b8af2fbcf4659" contextRef="c20220101to20220331_AwardTypeAxis_EmployeeStockMember" format="ixt-sec:durmonth">6</ix:nonNumeric> months</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; 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'; font-size: 10pt; font-style: italic;">RSUs:</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'; 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_27893998ace24d7cb0e5fa8a728fcf92" contextRef="c20230101to20230331_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_0b9e4755a19545e988f3c011792dba0c" contextRef="c20230101to20230331_AwardTypeAxis_RestrictedStockUnitsRSUMember_GranteeStatusAxis_ShareBasedPaymentArrangementBoardOfDirectorMember_RangeAxis_MaximumMember" format="ixt-sec:durwordsen">four-year</ix:nonNumeric> period. The RSUs we granted after June 2020 to our board of directors fully vest after <ix:nonNumeric name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" id="Fact_6ad8053af26d4d419b4294b9cd273b8f" contextRef="c20230101to20230331_AwardTypeAxis_RestrictedStockUnitsRSUMember_GranteeStatusAxis_ShareBasedPaymentArrangementBoardOfDirectorMember_RangeAxis_MinimumMember" format="ixt-sec:durwordsen">one year</ix:nonNumeric>. The weighted-average grant date fair value of RSUs granted to employees for the three months ended&#160;March 31, 2023 was $<ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" id="Fact_7654fd0b1d374d55b0c76914d3cd1ad7" contextRef="c20230101to20230331_AwardTypeAxis_RestrictedStockUnitsRSUMember_GranteeStatusAxis_ShareBasedPaymentArrangementEmployeeMember" unitRef="U004" decimals="2" scale="0" format="ixt:num-dot-decimal">39.85</ix:nonFraction>
    per share.</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'; font-size: 10pt; font-style: italic;">PRSUs:</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'; font-size: 10pt;">Beginning in 2020, we added PRSU awards to the compensation for our Chief Executive Officer, Dr. Brett Monia. In 2022, we added PRSU awards to the
    compensation for our other Section 16 officers. Beginning in 2023, we added PRSU awards to the compensation for all executive officers.</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'; font-size: 10pt;">Under the terms of the PRSUs we granted in 2020 through 2022, <span style="-sec-ix-hidden:Fact_3ea144f70898401099a1731ad0c7e39f"><span style="-sec-ix-hidden:Fact_b531c97d5a394e3f8a5454ecd82ddb93"><span style="-sec-ix-hidden:Fact_b2b6dbe875764e78b9cce0b8464216dd">one third</span></span></span> of the PRSUs may vest at the end of <ix:nonFraction name="ions:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods" id="Fact_22182278d2c74c399b1aa1ec24dcb90a" contextRef="c20230101to20230331_AwardTypeAxis_PerformanceSharesMember_GranteeStatusAxis_ExecutiveOfficerMember" unitRef="U008" 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_eaaa26558fcd4695b1458629faf19186" contextRef="c20230101to20230331_AwardTypeAxis_PerformanceSharesMember_GranteeStatusAxis_ExecutiveOfficerMember" format="ixt-sec:durwordsen">three years</ix:nonNumeric> 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, <ix:nonFraction name="ions:ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest" id="Fact_a18106d46f494438a0e064c9f9a96fbd" contextRef="c20230101to20230331_AwardTypeAxis_PerformanceSharesMember_GranteeStatusAxis_ExecutiveOfficerMember" unitRef="U001" decimals="INF" 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_2200a3292de944e78e0d6c8d840bacb1" contextRef="c20230101to20230331_AwardTypeAxis_PerformanceSharesMember_GranteeStatusAxis_ExecutiveOfficerMember_RangeAxis_MinimumMember" unitRef="U003" decimals="INF" scale="-2" format="ixt-sec:numwordsen">zero </ix:nonFraction>percentto <ix:nonFraction name="ions:ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest" id="Fact_ce7480294faa46eab25c9b702916942c" contextRef="c20230101to20230331_AwardTypeAxis_PerformanceSharesMember_GranteeStatusAxis_ExecutiveOfficerMember_RangeAxis_MaximumMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">150</ix:nonFraction> percent of the target number
    depending on our relative TSR.</div>
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  </div>
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  <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
    <div class="BRPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">15</div>

    </div>

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

    <div class="BRPFPageHeader">
      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>
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<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">Under the terms of the PRSUs we granted in 2023, 100 percent of the PRSUs may vest at the end of the three-year performance period based on our relative
    TSR as compared to a peer group of companies and as measured at the end of the 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 200 percent of the target number depending on our relative TSR.</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'; font-size: 10pt;">We determined the fair value of the PRSUs using a Monte Carlo model because the performance target is based on our relative TSR, which represents a
    market condition. The weighted-average grant date fair value of PRSUs granted to our executive officers for the three months ended&#160;March 31, 2023 and 2022 were $<ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" id="Fact_f686380f406d44659451af43ea4a98c6" contextRef="c20230101to20230331_AwardTypeAxis_PerformanceSharesMember_GranteeStatusAxis_ExecutiveOfficerMember" unitRef="U004" decimals="2" scale="0" format="ixt:num-dot-decimal">58.99</ix:nonFraction> and $<ix:nonFraction name="us-gaap:ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" id="Fact_f37b71af46f844b7971b1a2b89993315" contextRef="c20220101to20220331_AwardTypeAxis_PerformanceSharesMember_GranteeStatusAxis_ExecutiveOfficerMember" unitRef="U004" decimals="2" scale="0" format="ixt:num-dot-decimal">42.28</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'; font-size: 10pt;">The following table summarizes stock-based compensation expense for the three months ended&#160;March 31, 2023 and 2022 (in thousands):</div>
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<div style="text-align: justify; text-indent: 36pt;"><br />
  </div>
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<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" colspan="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">2023</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; font-size: 10pt; font-weight: bold;">2022</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'; 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">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AllocatedShareBasedCompensationExpense" id="Fact_99e0a32e2d2345afb5dae8769531813a" contextRef="c20230101to20230331_IncomeStatementLocationAxis_CostOfSalesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">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">
          <div style="color: #000000; font-family: 'Times New Roman'; 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: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Research, development and patent 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AllocatedShareBasedCompensationExpense" id="Fact_d17f71a28c014450810cc3b1536b5b8b" contextRef="c20230101to20230331_IncomeStatementLocationAxis_ResearchDevelopmentAndPatentExpensesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">19,567</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AllocatedShareBasedCompensationExpense" id="Fact_3c2e5d8e247446ac9584c5c2161ac0d5" contextRef="c20220101to20220331_IncomeStatementLocationAxis_ResearchDevelopmentAndPatentExpensesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">19,082</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: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Selling, general and administrative expense</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AllocatedShareBasedCompensationExpense" id="Fact_10a81038cb0946ad979fbbbc68e8f89e" contextRef="c20230101to20230331_IncomeStatementLocationAxis_SellingGeneralAndAdministrativeExpensesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">7,262</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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AllocatedShareBasedCompensationExpense" id="Fact_763195b2b34c488bb094472395ab650d" contextRef="c20220101to20220331_IncomeStatementLocationAxis_SellingGeneralAndAdministrativeExpensesMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">6,994</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%; padding-bottom: 4px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AllocatedShareBasedCompensationExpense" id="Fact_86792c009d4e41b3a08f1d4f8e56e11b" contextRef="c20230101to20230331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">26,948</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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:AllocatedShareBasedCompensationExpense" id="Fact_dff8aaed89804850bc5c9157ed3f5de6" contextRef="c20220101to20220331" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">26,236</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>
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  <ix:continuation id="Text_8b6a4931d32c4ab3975dbfab9a804c9836">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">As of March 31, 2023,
    total unrecognized estimated stock-based compensation expense related to non-vested stock options, RSUs and PRSUs was $<ix:nonFraction name="us-gaap:EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedStockOptions" id="Fact_6ffe2ab146ea4bd888ad8a1bb3fc3738" contextRef="c20230331_AwardTypeAxis_EmployeeStockOptionMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">60.2</ix:nonFraction> million, $<ix:nonFraction name="us-gaap:EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedShareBasedAwardsOtherThanOptions" id="Fact_221a3013ba19446cad9c335f9391fa1a" contextRef="c20230331_AwardTypeAxis_RestrictedStockUnitsRSUMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">79.1</ix:nonFraction> million and $<ix:nonFraction name="us-gaap:EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedShareBasedAwardsOtherThanOptions" id="Fact_1a5a87c9d0c04b5799a90b3d2965c63f" contextRef="c20230331_AwardTypeAxis_PerformanceSharesMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">9.5</ix:nonFraction> million, respectively. Our
    actual expenses may differ from these estimates because we will adjust our unrecognized stock-based compensation expense for future forfeitures, including any PRSUs that do not vest. We expect to recognize the cost of stock-based compensation expense
    related to our non-vested stock options, RSUs and PRSUs over a weighted average amortization period of <ix:nonNumeric name="us-gaap:EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1" id="Fact_13a68deb2d8d496a9b99b31f4abcfe12" contextRef="c20230101to20230331_AwardTypeAxis_EmployeeStockOptionMember" format="ixt-sec:duryear">1.4</ix:nonNumeric> years, <ix:nonNumeric name="us-gaap:EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1" id="Fact_94356ff2a4564b669110ba6365630dc9" contextRef="c20230101to20230331_AwardTypeAxis_RestrictedStockUnitsRSUMember" format="ixt-sec:duryear">1.8</ix:nonNumeric> years and <ix:nonNumeric name="us-gaap:EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1" id="Fact_715166969b8f40d5bb56857e5eca4ce6" contextRef="c20230101to20230331_AwardTypeAxis_PerformanceSharesMember" format="ixt-sec:duryear">2.2</ix:nonNumeric> years, respectively.</div>
</ix:continuation></div>

  <div><br />
  </div>
<div><ix:nonNumeric name="us-gaap:IncomeTaxDisclosureTextBlock" id="Text_5d168265bebe4eef9cbf660ffa2537c4" contextRef="c20230101to20230331" escape="true" continuedAt="Text_c410dd5bda4f48008899d33a99064a981">
<div style="display:none;"><br /></div>
<div style="text-align: left; text-indent: -36pt; margin-left: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">9.&#160; Income Taxes</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'; font-size: 10pt;">Beginning in 2022, the Tax Cuts and Jobs Act of 2017, or TCJA, requires taxpayers to amortize research and development expenditures over
    five years pursuant to Internal Revenue Code, or IRC, Section 174. Additionally, we expect to reflect the royalty purchase agreement with Royalty Pharma as a taxable sale, requiring us to include the proceeds from the sale, net of currently deductible
    issuance costs, as taxable income in 2023.</div>
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<div><br />
  </div>
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  <ix:continuation id="Text_c410dd5bda4f48008899d33a99064a984">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We recorded income tax expense of $<ix:nonFraction name="us-gaap:IncomeTaxExpenseBenefit" id="Fact_4b3f01cf09d94228871fc7985d1e7730" contextRef="c20230101to20230331" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">11.4</ix:nonFraction>
    million and $<ix:nonFraction name="us-gaap:IncomeTaxExpenseBenefit" id="Fact_60f4bba6820147aa9e2ebb581601b708" contextRef="c20220101to20220331" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">1.1</ix:nonFraction> million for the three months ended March 31, 2023 and 2022, respectively. The increase in income tax expense for the three
    months ended March 31, 2023, compared to the same period in 2022, relates primarily to the impact of the Royalty Pharma transaction. </div>
</ix:continuation></div>

  <div><br />
  </div>
<div><ix:nonNumeric name="us-gaap:OtherLiabilitiesDisclosureTextBlock" id="Text_f2a697cc2a48421a914d3e69877cc71e" contextRef="c20230101to20230331" escape="true" continuedAt="Text_84ad19fcc1734d8084f483e2f868e7a91">
<div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">10. Liability Related to Sale of Future Royalties</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'; font-size: 10pt;">In January 2023, we entered into a royalty purchase agreement with Royalty Pharma to monetize a portion of our future SPINRAZA and
    pelacarsen royalties we are entitled to under our arrangements with Biogen and Novartis, respectively. As a result, we received an upfront payment of $<ix:nonFraction name="ions:UpfrontRoyaltyPaymentReceived" id="Fact_378c023c31584e55b0617bdf49309947" contextRef="c20230101to20230131_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember" unitRef="U002" decimals="-6" scale="6" format="ixt:num-dot-decimal">500</ix:nonFraction>
    million and we are eligible to receive up to $<ix:nonFraction name="ions:MaximumAmountOfPaymentsReceivableForAdditionalMilestones" id="Fact_45c4a4d71b5f46aa8fc6a9fd8e84328e" contextRef="c20230331_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember" unitRef="U002" decimals="-6" scale="6" format="ixt:num-dot-decimal">625</ix:nonFraction> million in additional milestone payments. Under the terms of the agreement, Royalty Pharma will
    receive <ix:nonFraction name="ions:PercentageOfRoyaltyPaymentsPaidOnAnnualSalesOfMedicine" id="Fact_01f145be530749a2b5f41c92469f3150" contextRef="c20230331_ProductOrServiceAxis_SpinrazaMember_RangeAxis_MinimumMember_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">25</ix:nonFraction> percent of our SPINRAZA royalty payments from 2023 through 2027, increasing to <ix:nonFraction name="ions:PercentageOfRoyaltyPaymentsPaidOnAnnualSalesOfMedicine" id="Fact_4defe32cd3804cbb97e4c7a2e3a297be" contextRef="c20230331_ProductOrServiceAxis_SpinrazaMember_RangeAxis_MaximumMember_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">45</ix:nonFraction> percent of royalty payments in 2028, on up to $<ix:nonFraction name="ions:MaximumAmountOfAnnualSalesOnWhichRoyaltyPaymentsArePaid" id="Fact_4af0123d3f9a49d28566cdb7b703162e" contextRef="c20230331_ProductOrServiceAxis_SpinrazaMember_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember" unitRef="U002" decimals="-8" scale="9" format="ixt:num-dot-decimal">1.5</ix:nonFraction> billion in annual sales. In
    addition, Royalty Pharma will receive <ix:nonFraction name="ions:PercentageOfRoyaltyPaymentsPaidOnAnnualSalesOfMedicine" id="Fact_5ab159c91cd6498eabdc7aec74f5b116" contextRef="c20230331_ProductOrServiceAxis_PelacarsenMember_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">25</ix:nonFraction> percent of any future royalty payments on pelacarsen, our medicine in development to treat patients
    with elevated lipoprotein(a), or Lp(a), and cardiovascular disease. Royalty Pharma&#8217;s royalty interest in SPINRAZA will revert to us after total SPINRAZA royalty payments to Royalty Pharma reach either $<ix:nonFraction name="ions:MaximumRoyaltyPaymentsMadeBeforeRoyaltyInterestRevertsBack" id="Fact_8efbfdbd4aec4c57ba48a38ed1338a40" contextRef="c20230331_ProductOrServiceAxis_SpinrazaMember_RangeAxis_MinimumMember_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember" unitRef="U002" decimals="-6" scale="6" format="ixt:num-dot-decimal">475</ix:nonFraction> million or $<ix:nonFraction name="ions:MaximumRoyaltyPaymentsMadeBeforeRoyaltyInterestRevertsBack" id="Fact_d8115145c7914c85b8aa1e8af6fd697a" contextRef="c20230331_ProductOrServiceAxis_SpinrazaMember_RangeAxis_MaximumMember_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember" unitRef="U002" decimals="-6" scale="6" format="ixt:num-dot-decimal">550</ix:nonFraction> million, depending on the timing and occurrence of FDA approval of
    pelacarsen.</div>
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  </div>
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  <ix:continuation id="Text_84ad19fcc1734d8084f483e2f868e7a94" continuedAt="Text_84ad19fcc1734d8084f483e2f868e7a95">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We recorded the upfront payment of $<ix:nonFraction name="ions:UpfrontRoyaltyPaymentReceived" id="Fact_9289646b66ea4d879d32f2749df14834" contextRef="c20230101to20230131_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember" unitRef="U002" decimals="-6" scale="6" format="ixt:num-dot-decimal">500</ix:nonFraction>
    million as a liability related to the sale of future royalties, net of transaction costs of $<ix:nonFraction name="ions:PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties" id="Fact_b8a78efb0bd340eb9b74a4c718aade51" contextRef="c20230101to20230331_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember" unitRef="U002" decimals="-5" scale="6">10.4</ix:nonFraction> million, which we are amortizing over the
    estimated life of the arrangement using the effective interest rate method. We recognize royalty revenue in the period in which the counterparty sells the related product and recognizes the related revenue. We record royalty payments made to Royalty
    Pharma as a reduction of the liability.</div>
</ix:continuation>
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  <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
    <div class="BRPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">16</div>

    </div>

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

    <div class="BRPFPageHeader">
      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </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'; font-size: 10pt;">We estimate the effective interest rate used to record interest expense under this agreement based on the estimate of future royalty
    payments to Royalty Pharma. As of March 31, 2023, the estimated effective interest rate under the agreement was <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateEffectivePercentage" id="Fact_b086ad26f3df4c96a5fb5a381fd3f7e6" contextRef="c20230331_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember" unitRef="U003" decimals="3" scale="-2" format="ixt:num-dot-decimal">13.5</ix:nonFraction> percent.</div>
</ix:continuation>

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</ix:continuation>
  <ix:continuation id="Text_84ad19fcc1734d8084f483e2f868e7a98" continuedAt="Text_84ad19fcc1734d8084f483e2f868e7a99"><ix:nonNumeric name="us-gaap:OtherNoncurrentLiabilitiesTableTextBlock" id="Text_96e6cdff125b48ec820d34ebadba6671" contextRef="c20230101to20230331" escape="true" continuedAt="Text_1150a9aed3e8494190a98c831bd12bfc1">
<div style="display:none;"><br /></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">The following is a summary of our liability related to sale of future royalties for the three
    months ended March 31, 2023 (in thousands):</div>
</ix:nonNumeric></ix:continuation>
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<div><br />
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</ix:continuation></ix:continuation>
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<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; text-align: left; color: #000000; width: 100%;" class="cfttable">


  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;">Proceeds from sale of future 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="font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;"><ix:nonFraction name="ions:ProceedsFromSaleOfFutureRoyalties" id="Fact_7a91cc925cbe4e289100163fed10eb8f" contextRef="c20230101to20230331_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">500,000</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%; padding-bottom: 2px;">
          <div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;">Interest expense related to sale of future royalties</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="font-family: 'Times New Roman'; font-size: 10pt;"><ix:nonFraction name="ions:InterestExpenseRelatedToSaleOfFutureRoyalties" id="Fact_8e2a0dc656c042c0beb05848a9d90cc8" contextRef="c20230101to20230331_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">15,363</ix:nonFraction></div>
        </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>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;">Liability related to sale of future royalties as of March 31, 2023</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="font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" colspan="1">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;"><ix:nonFraction name="ions:LiabilityRelatedToSaleOfFutureRoyaltiesGross" id="Fact_bc68084a14554c4b9e5d028dcee5c291" contextRef="c20230331_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">515,363</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%; padding-bottom: 2px;">
          <div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;">Net issuance costs related to sale of future royalties as of March 31, 2023</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="font-family: 'Times New Roman'; font-size: 10pt;">(<ix:nonFraction name="us-gaap:DeferredFinanceCostsNet" id="Fact_c211cdd46ff84aefa16bbfccaf2b3ea6" contextRef="c20230331_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">10,282</ix:nonFraction></div>
        </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="font-family: 'Times New Roman'; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td valign="bottom" style="vertical-align: top; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;">Net liability related to sale of future royalties as of March 31, 2023</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="font-family: 'Times New Roman'; 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="font-family: 'Times New Roman'; font-size: 10pt;"><ix:nonFraction name="ions:LiabilityRelatedToSaleOfFutureRoyaltiesNet" id="Fact_b429946842f746a59ab4c99405afe9a0" contextRef="c20230331_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember" unitRef="U002" decimals="-3" scale="3" format="ixt:num-dot-decimal">505,081</ix:nonFraction></div>
        </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">&#160;</td>

  </tr>


</table>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">There are numerous factors, most of which are not within our control, that could materially impact the amount and timing of royalty
    payments from Biogen and Novartis, and result in changes to our estimate of future royalty payments to Royalty Pharma. Such factors include, but are not limited to the commercial sales of SPINRAZA, the regulatory approval and commercial sales of
    pelacarsen, competing products or other significant events.</div>
</ix:continuation></div>

  <div style="text-align: left; font-family: Calibri; font-size: 12pt;"><br />
  </div>
<div><ix:nonNumeric name="us-gaap:DebtDisclosureTextBlock" id="Text_932c025cb1a047c69adb81a74fc1d444" contextRef="c20230101to20230331" escape="true" continuedAt="Text_501f1414c5124ff0a45d26930d5433051">
<div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">11. 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'; font-size: 10pt; font-style: italic;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_0e3676949d7c473e97d1d20974f8f44c" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">0</ix:nonFraction> Percent
    Convertible Senior Notes and Call Spread</div>
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<div><br />
  </div>
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<div style="text-align: justify; text-indent: 36pt; font-family: Times; font-size: 10pt;">In April 2021, we completed a $<ix:nonFraction name="us-gaap:DebtInstrumentFaceAmount" id="Fact_33400ed1eb934bb0bd69010fd9108f10" contextRef="c20210430_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">632.5</ix:nonFraction> million offering of
    convertible senior notes. We used a portion of the net proceeds from the issuance of the <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_cf548beac2bc489f86139c6d963e1ba2" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">0</ix:nonFraction>% Notes to repurchase $<ix:nonFraction name="us-gaap:DebtInstrumentRepurchasedFaceAmount" id="Fact_2e15cbbe49ad4e279285c65539f5b3ec" contextRef="c20210430_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">247.9</ix:nonFraction> million in principal of our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_751dd10e214d4321b273d4f49ecf3f6d" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">1</ix:nonFraction>% Notes for $<ix:nonFraction name="us-gaap:RepaymentsOfConvertibleDebt" id="Fact_f12e3210b54c489abc9b8db2ec94ece2" contextRef="c20210401to20210430_DebtInstrumentAxis_ConvertibleSeniorNotes1PercentMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">257.0</ix:nonFraction> million.</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'; font-size: 10pt;">At March 31, 2023, we had the following <span style="font-family: Times; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_16e7fa8c1a5840b1ac5c8aa87a6ecf14" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">0</ix:nonFraction>%</span> Notes outstanding (in millions except interest rate and price per share data):</div>
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<div><br />
  </div>
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  <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="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_72099b84515a4987a6ed39e66479bffc" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">0</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'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentCarryingAmount" id="Fact_a67ad95abe2d4dd9908f49e9f2b5ff38" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">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'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DeferredFinanceCostsNet" id="Fact_5ec7acd6c2514e8cabe31debb2a3b6a9" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">9.5</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'; 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'; font-size: 10pt;"><span style="-sec-ix-hidden:Fact_edbb9fb31e834f86ad026d22e567df04">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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_eb33a4a1dda248649a730b726ee6e4ab" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateEffectivePercentage" id="Fact_63a78b08d33541519708442f3d1e2957" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="3" scale="-2" format="ixt:num-dot-decimal">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'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentConvertibleConversionPrice1" id="Fact_95d4f72d952f49fb80b34fdc489ad77a" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U004" decimals="2" scale="0" format="ixt:num-dot-decimal">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'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtInstrumentConvertibleConversionPriceIncludingCallSpread" id="Fact_81a2de43ec8947979830016c7ae89c30" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U004" decimals="2" scale="0" format="ixt:num-dot-decimal">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'; 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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtInstrumentConvertibleSharesSubjectToConversion" id="Fact_88ccdeff6aeb43b2b0d735cbf3651c87" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U001" decimals="-5" scale="6" format="ixt:num-dot-decimal">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>
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<div style="text-align: justify; text-indent: 36pt; font-family: Calibri; font-size: 12pt;"><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'; 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-family: Times; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_8d1a4d03d8144e47b63f8e4fe5edea5e" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">0</ix:nonFraction>%</span>
    Notes by increasing the effective conversion price on our <span style="font-family: Times; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_f647ae8c9e9d49c78dd3b8a8f601fbe6" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">0</ix:nonFraction>%</span> Notes. We increased our
    effective conversion price to $<ix:nonFraction name="ions:DebtInstrumentConvertibleConversionPriceIncludingCallSpread" id="Fact_8f89399b6ebc43edbd9bf57eae0f6a00" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U004" decimals="2" scale="0" format="ixt:num-dot-decimal">76.39</ix:nonFraction> with the same number of underlying shares as our <span style="font-family: Times; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_e1f0bf581c4e4cd09ceef3c4a8c66d8b" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">0</ix:nonFraction>%&#160;</span>Notes. The call spread cost us $<ix:nonFraction name="ions:CallSpread" id="Fact_adc134900f3e4b2a8095bb94c51ff448" contextRef="c20210401to20210430_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">46.9</ix:nonFraction>
    million, of which $<ix:nonFraction name="us-gaap:PaymentsForHedgeFinancingActivities" id="Fact_27fba3d5bc6e4961a0ec541d9ce880e5" contextRef="c20210401to20210430_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">136.7</ix:nonFraction> million was for the note hedge purchase, offset by $<ix:nonFraction name="us-gaap:ProceedsFromIssuanceOfWarrants" id="Fact_fae589c1422f409bab0ef5a3d362a9d2" contextRef="c20210401to20210430_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">89.8</ix:nonFraction> million we received for selling the warrants. Similar to our <span style="font-family: Times; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_f275e8ed60f84ce58a3fb217a7effde2" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">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-family: Times; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_9a0025dc07b948759f15259d7f5c6fdb" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">0</ix:nonFraction>%</span> Notes. The note hedges will expire upon maturity of the <span style="font-family: Times; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_26151b0f7f634b91a20e7b74ac5f57d7" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">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-family: Times; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_7bd39b60327b4b2a961691b5ae863d0a" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">0</ix:nonFraction>%</span> Notes. The holders of the <span style="font-family: Times; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_c3580cc62da242428fa842ae2cebc7fc" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">0</ix:nonFraction>%</span> Notes do not have any rights with respect to the note hedges and warrants.</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; 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 condensed
    consolidated balance sheets. Refer to Part IV, Item 15, Note 1 of our audited financial statements included in our Annual Report on Form 10-K for the year ended December 31, 2022 for our Call Spread accounting policy. 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 style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">17</div>

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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

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<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_a33ce35bdd374749b6f33e880968b6c9" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal">0.125</ix:nonFraction> Percent Convertible
    Senior Notes and Call Spread</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">At March 31, 2023, we had the following <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_c91fd8cfcca146eeaee60bbae9843a5c" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal">0.125</ix:nonFraction>%
    Notes outstanding with interest payable semi-annually (in millions except interest rate and price per share data):</div>
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<table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; 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="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_c74c7559f3794aff8fd34e6e71dc7e36" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal">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'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentCarryingAmount" id="Fact_8fdb29e27b1249be96c416b7e1afbe6f" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">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>

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    <td valign="bottom" style="vertical-align: top; width: 88%;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DeferredFinanceCostsNet" id="Fact_ef8abebcb9cd4d2c8d22e438aa20d596" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">3.8</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: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><span style="-sec-ix-hidden:Fact_9ad2e8b4fef74d3cab598aa38f5df4fd">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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_5f715031591b4fe6a0024076fc0b6dae" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal">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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateEffectivePercentage" id="Fact_4a8586e56b5f42e494ac20b9ebaf16ba" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="3" scale="-2" format="ixt:num-dot-decimal">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'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentConvertibleConversionPrice1" id="Fact_cd9641bba27d48d89431b73d453aae5e" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U004" decimals="2" scale="0" format="ixt:num-dot-decimal">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'; 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'; 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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtInstrumentConvertibleConversionPriceIncludingCallSpread" id="Fact_4825eb43f8064051b13d428922900c94" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U004" decimals="2" scale="0" format="ixt:num-dot-decimal">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'; 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'; font-size: 10pt;"><ix:nonFraction name="ions:DebtInstrumentConvertibleSharesSubjectToConversion" id="Fact_1a6966cb93514cde8fc57a63185f51f0" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U001" decimals="-5" scale="6" format="ixt:num-dot-decimal">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>
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<div style="text-align: justify; text-indent: 36pt; font-family: Calibri; font-size: 12pt;"><br />
  </div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">In conjunction with the issuance of our </span><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_c6a7865d9b5b492081a7f522b07e11fa" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal">0.125</ix:nonFraction>%<span style="font-family: 'Times New Roman'; font-size: 10pt; 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_866d978c915841dea195724419fef4e3" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal">0.125</ix:nonFraction>%
    Notes by increasing the effective conversion price on our <ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_14b15285e173484ebef7a46abc2036df" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal">0.125</ix:nonFraction>% Notes<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">. We increased our effective conversion price to $123.38 with the same number of underlying shares as our </span><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_12dd621b8581486fae2021f59964df1e" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal">0.125</ix:nonFraction>%<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> Notes. The call spread cost us $</span><ix:nonFraction name="ions:CallSpread" id="Fact_aa24cd7f5c614512b1647e86a78f4031" contextRef="c20191201to20191231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">52.6</ix:nonFraction><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> million, of which $</span><ix:nonFraction name="us-gaap:PaymentsForHedgeFinancingActivities" id="Fact_f3981ee582ef4443af493f8da7ca2b64" contextRef="c20191201to20191231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">108.7</ix:nonFraction><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> million was for the note hedge purchase, offset by $</span><ix:nonFraction name="us-gaap:ProceedsFromIssuanceOfWarrants" id="Fact_66c802772ac04d93a9ee2afafef489b6" contextRef="c20191201to20191231_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U002" decimals="-5" scale="6" format="ixt:num-dot-decimal">56.1</ix:nonFraction><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> million we received for selling the warrants. Similar to our </span><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_114816fa082a426dba291250c81fb6a1" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal">0.125</ix:nonFraction>% Notes<span style="font-family: 'Times New Roman'; font-size: 10pt; 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_f94762bb86964ced9cbdb14a7295aad0" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal">0.125</ix:nonFraction>% Notes<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">. The note hedges will expire upon maturity of the </span><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_b48f6a51f5c64b7e8214ed3445df6131" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal">0.125</ix:nonFraction>% Notes<span style="font-family: 'Times New Roman'; font-size: 10pt; 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_b72359aeedb54807b8b03fc26f0a7bfa" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal">0.125</ix:nonFraction>% Notes<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">. The holders of
      the </span><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_4e836a7f0c1d4f8ca2688d3e4a6dfede" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal">0.125</ix:nonFraction>% Notes<span style="font-family: 'Times New Roman'; font-size: 10pt; 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'; 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
    condensed consolidated balance sheets. 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 style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;">Other Terms of Convertible Senior Notes</div>
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<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">The </span><span style="font-family: Times; font-size: 10pt;"><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_2e4a8b6cc00b43f29c990216f40a4bb7" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">0</ix:nonFraction>%</span><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> and </span><ix:nonFraction name="us-gaap:DebtInstrumentInterestRateStatedPercentage" id="Fact_8339e5213d28400e84342b3e1d73f657" contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="5" scale="-2" format="ixt:num-dot-decimal">0.125</ix:nonFraction>%<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> 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 </span><ix:nonFraction name="ions:DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange" id="Fact_a38abeae4ec74a3eaf19e2d07a941668" contextRef="c20230101to20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal"><ix:nonFraction name="ions:DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAsPurchasePriceUponOccurrenceOfFundamentalChange" id="Fact_229a2def62c24eed980d9982856538b0" contextRef="c20230101to20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember" unitRef="U003" decimals="2" scale="-2" format="ixt:num-dot-decimal">100</ix:nonFraction></ix:nonFraction> percent<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> of the principal amount of the notes to be purchased, plus any accrued and unpaid interest.</span></div>
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<div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">12. Legal Proceedings</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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 we consider the potential loss from any legal proceeding to be probable and we can reasonably estimate the amount, we accrue a liability for the estimated loss. The outcome of
    any proceeding is not determinable in advance. Therefore, we are required to use significant judgment to determine the probability of a loss and whether the amount of the loss is reasonably estimable. Our assessment of a potential liability and the
    amount of accruals we 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>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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 Shumacher Action. The complaint names Ionis&#8217; board of directors, or the Board, as defendants and names Ionis as a nominal defendant. The Shumacher Action Plaintiff
    asserts a breach of fiduciary duty claim against the Board for awarding and receiving allegedly excessive compensation. The Shumacher Action Plaintiff also asserts an unjust enrichment claim against the non-executive 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. On March 18, 2022, Ionis and the Board moved to dismiss the complaint.
    On May 24, 2022, the parties entered into a Stipulation and Agreement of Compromise, Settlement and Release.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">On May 25, 2022, another purported stockholder of Ionis filed a stockholder derivative complaint also in the Delaware Court of Chancery
    captioned Robert S. Cohen, et al. v. Joseph Loscalzo, et al., C.A. No. 2022-0453, or the Cohen Action. The complaint names the Board as defendants and names Ionis as a nominal defendant. The Cohen Action Plaintiff asserts claims for breach of fiduciary
    duty, unjust enrichment, aiding and abetting breaches of fiduciary duty, and waste against the Board for awarding and receiving allegedly excessive non-executive director compensation for the years 2018, 2019, and 2020. On June 2, 2022, the Cohen
    Action Plaintiff filed a motion to consolidate the related Cohen Action and Shumacher Action. On July 5, 2022, the Court denied the motion to consolidate in favor of the settlement pending in the Shumacher Action.</div>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">On July 18, 2022, Ionis filed a Form 8-K disclosing the pending settlement and attaching the Notice of Pendency of Settlement of Action.
    On September 21, 2022, the Court held a hearing to consider whether the terms of the settlement should be approved, at which hearing the Cohen Action plaintiff objected to the settlement. At the conclusion of the hearing, the Court declined to approve
    the settlement and directed the parties to meet and confer on the issue of the scope of the release. On February 7, 2023, the parties entered into an Amended Stipulation and Agreement of Compromise, Settlement and Release, which folded the Cohen Action
    into the settlement, or the Revised Settlement. The settlement did not have a material impact on our condensed consolidated financial statements. On April 24, 2023, the Court issued an Order and Final Judgment approving the Revised Settlement and
    dismissing the Shumacher and Cohen Actions, and all claims contained therein, with prejudice. The Order does not contain any admission of wrongdoing by any defendant.</div>
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  <div><a id="ITEM2MDAQ1"><!--Anchor--></a></div>
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    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">MANAGEMENT&#8217;S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS</div>
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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;">In this Report on Form 10-Q, unless the context requires otherwise, &#8220;Ionis,&#8221; &#8220;Company,&#8221; &#8220;we,&#8221; &#8220;our,&#8221; and &#8220;us,&#8221; means
    Ionis Pharmaceuticals, Inc. and its wholly owned affiliate, Akcea Therapeutics, Inc.</div>

  <div><br />
  </div>

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

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">In addition to historical information contained in this Report on Form 10-Q, the Report includes forward-looking
    statements regarding our business and the therapeutic and commercial potential of QALSODY (tofersen), SPINRAZA (nusinersen), TEGSEDI (inotersen), WAYLIVRA (volanesorsen), eplontersen, olezarsen, donidalorsen, ION363, pelacarsen, bepirovirsen, our
    technologies and our other 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 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 and described in additional detail in our annual report on Form 10-K for the year ended December 31, 2022, which is on file with the U.S. Securities and Exchange Commission and is available from us, and those identified within Part II Item 1A. Risk Factors of this
    Report. 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>

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

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">We were founded over 30 years ago to deliver innovative medicines for
      diseases with great medical need. Today, we are building on our advancements in RNA-targeted therapeutics to move us closer to achieving our vision to be the leader in genetic medicines. We believe our medicines have the potential to pioneer new
      markets, change standards of care and transform the lives of people with devastating diseases</span>. We currently have four marketed medicines: QALSODY, SPINRAZA, TEGSEDI and WAYLIVRA. <span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">On April 25, 2023, the U.S. Food and Drug Administration, or FDA, granted Biogen accelerated approval of QALSODY for the treatment of superoxide dismutase 1 amyotrophic lateral sclerosis, or SOD1-ALS. Additionally, the FDA accepted
      our New Drug Application, or NDA, of eplontersen for polyneuropathy caused by hereditary TTR amyloidosis, or ATTRv-PN. Eplontersen&#8217;s Prescription Drug User Fee Act, or PDUFA, date is December 22, 2023. We also have a rich innovative late- and
      mid-stage pipeline primarily focused on our leading cardiovascular and neurology franchises. We recently expanded our Phase 3 pipeline to seven programs across nine indications following the start of GSK&#8217;s bepirovirsen hepatitis B program.</span></div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">Our multiple sources of revenue and strong balance sheet enable us to
      continue investing in our commercial readiness efforts for multiple late-stage programs and our innovative pipeline. 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</span>.</div>

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

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">SPINRAZA is the global market leader for the treatment of patients with
      spinal muscular atrophy, or SMA, a progressive, debilitating and often fatal genetic disease. Biogen is our partner responsible for commercializing SPINRAZA worldwide</span>. From inception through March 31, 2023, we have earned more than $1.9 billion in revenues from our SPINRAZA collaboration, including more than $1.4 billion in royalties on sales of SPINRAZA.</div>

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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">TEGSEDI is a once weekly, self-administered subcutaneous medicine
      approved in the U.S., Europe, Canada and Brazil for the treatment of patients with</span> polyneuropathy caused by hereditary polyneuropathy, or ATTRv-PN, a debilitating, progressive, and fatal disease. We launched TEGSEDI in the United States, or
    U.S., and the European Union, or EU, in late 2018. <span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">In 2021, we began selling TEGSEDI in Europe through our distribution agreement with Swedish Orphan Biovitrum AB, or Sobi,
      and 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</span>.</div>

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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. In Latin America, PTC is commercializing WAYLIVRA in Brazil for two indications, FCS and familial partial lipodystrophy, or FPL, and is pursuing access in additional Latin
    American countries through its exclusive license agreement with us.</div>

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  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">QALSODY is an antisense medicine that received accelerated approval in
      April 2023 from the FDA for the treatment of patients with SOD1-ALS, a rare, neurodegenerative disorder that causes progressive loss of motor neurons leading to death. The European Medicines Agency, or EMA, is currently reviewing </span>QALSODY<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> for approval in the EU.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;">Medicines in Registration and Phase 3 Studies</div>

  <div><br />
  </div>

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

  <div><br />
  </div>

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    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;">Eplontersen: <span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">our medicine in development for transthyretin amyloidosis, or ATTR</span></div>
        </td>

  </tr>


</table>
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    <td style="width: 54pt;"></td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We are currently conducting the Phase 3 NEURO-TTRansform study in patients with ATTRv-PN, the Phase 3 CARDIO-TTRansform study in patients with ATTR cardiomyopathy, or
            ATTR-CM, and additional studies supporting our ATTR development program</div>
        </td>

  </tr>


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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">In March 2023, the FDA accepted the NDA for eplontersen in the U.S. for patients with ATTRv-PN with a PDUFA date of December 22, 2023</div>
        </td>

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


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    <td style="width: 72pt;"></td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">In April 2023, we presented positive week-35 and week-66 data from the Phase 3 NEURO-TTRansform study in patients with ATTRv-PN at the American Academy of Neurology
            Annual Meeting</div>
        </td>

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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;">Olezarsen: our medicine in development for FCS and severe hypertriglyceridemia, or SHTG</div>
        </td>

  </tr>


</table>
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    <td style="width: 54pt;"></td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We are currently conducting a broad Phase 3 development program for olezarsen that includes the Phase 3 BALANCE study in patients with FCS and three Phase 3 studies
            supporting development for the treatment of SHTG: CORE, CORE2 and ESSENCE</div>
        </td>

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    <td style="width: 72pt;"></td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We remain on track for data from the Phase 3 BALANCE FCS study in the second half of 2023</div>
        </td>

  </tr>


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    <td style="width: 72pt;"></td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;">The <span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">FDA granted olezarsen fast track designation for the treatment of patients with FCS</span></div>
        </td>

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    <td style="width: 72pt;"></td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;">In <span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">the second half of 2022, we expanded our Phase 3 program for SHTG when we initiated CORE2, a
              confirmatory Phase 3 study of olezarsen in patients with SHTG and ESSENCE, a supporting Phase 3 study of olezarsen in patients with SHTG or hypertriglyceridemia and atherosclerotic cardiovascular disease</span></div>
        </td>

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  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; 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; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;">Donidalorsen: our medicine in development for hereditary angioedema, or HAE</div>
        </td>

  </tr>


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


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    <td style="width: 54pt;"></td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We are currently conducting the Phase 3 OASIS-HAE study in patients with HAE and the Phase 3 OASIS-Plus supportive study for HAE patients previously treated with other
            prophylactic therapies</div>
        </td>

  </tr>


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


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    <td style="width: 72pt;"></td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;">We remain on track to complete enrollment in the Phase 3 OASIS-HAE study in mid-2023 with data expected in the first half of 2024</div>
        </td>

  </tr>


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


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    <td style="width: 72pt;"></td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We reported positive data from the Phase 2 study and Phase 2 open-label extension, or OLE, study throughout 2022 and early 2023</div>
        </td>

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  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; 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; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;">ION363: our medicine in development for amyotrophic lateral sclerosis, or ALS, with mutations in the fused in sarcoma gene, or FUS</div>
        </td>

  </tr>


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    <td style="width: 54pt;"></td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We are currently conducting a Phase 3 study of ION363 in juvenile and adult patients with FUS-ALS</div>
        </td>

  </tr>


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  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; 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; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;">QALSODY: our medicine in development for superoxide dismutase 1 ALS, or SOD1-ALS</div>
        </td>

  </tr>


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    <td style="width: 54pt;"></td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">Biogen is developing </span>QALSODY<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">, including conducting the ongoing Phase 3 ATLAS study in presymptomatic SOD1 patients</span></div>
        </td>

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    <td style="width: 72pt;"></td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;">The FDA granted Biogen accelerated approval of QALSODY for patients with SOD1-ALS</div>
        </td>

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


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    <td style="width: 72pt;"></td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;">The EMA is currently reviewing QALSODY&#8217;s Marketing Authorization Application, or MAA, in the EU</div>
        </td>

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    <td style="width: 72pt;"></td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">In June 2022, Biogen presented new positive data from the ongoing VALOR OLE study at the European Network to Cure ALS, or ENCALS, meeting. These data were included in
            the NDA filing in the U.S. and MAA filing in the EU</div>
        </td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;">Pelacarsen: <span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">our medicine in development to treat patients with elevated lipoprotein(a), or Lp(a) and
              cardiovascular disease</span></div>
        </td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Novartis is developing pelacarsen, including conducting the ongoing Lp(a) HORIZON Phase 3 cardiovascular outcome study in patients with established cardiovascular
            disease and elevated Lp(a)</div>
        </td>

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


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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">In July 2022, Novartis achieved full enrollment in the Lp(a) HORIZON study</div>
        </td>

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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Bepirovirsen: our medicine in development for hepatitis B virus, or HBV</div>
        </td>

  </tr>


</table>
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    <td style="width: 54pt;"></td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">GSK is developing bepirovirsen, including conducting the ongoing B-Well Phase 3 program in patients with HBV</div>
        </td>

  </tr>


</table>
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    <td style="width: 72pt;"></td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">In 2022, GSK presented positive data from the Phase 2b B-Clear study of bepirovirsen demonstrating potential for functional cures in patients with chronic HBV</div>
        </td>

  </tr>


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  <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
    <div class="BRPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">21</div>

    </div>

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

    <div class="BRPFPageHeader">
      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

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

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">We prepare our condensed 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. 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 />
  </div>

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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Assessing the propriety of revenue recognition and associated deferred revenue; and</div>
        </td>

  </tr>


</table>
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  <tr>

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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">There have been no other material changes to our critical accounting policies and estimates from the information provided in Item 7,
    &#8220;Management&#8217;s Discussion and Analysis of Financial Condition and Results of Operations&#8221; included in our Annual Report on Form 10-K for the year ended December 31, 2022.</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"><a id="ResultsofOperations"><!--Anchor--></a>Results of Operations</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">The following is a summary of our financial results (in millions):</div>

  <div><br />
  </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="6">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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'; font-size: 10pt; font-weight: bold;">2023</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'; font-size: 10pt; font-weight: bold;">2022</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">&#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; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;">130.5</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'; 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'; font-size: 10pt;">141.9</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; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;">244.7</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">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">199.4</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'; 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'; 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'; font-size: 10pt;">(114.1</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'; 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'; 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'; font-size: 10pt;">(57.5</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'; font-size: 10pt;">)</div>
        </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'; 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'; 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'; font-size: 10pt;">(124.3</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'; 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'; 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'; font-size: 10pt;">(65.2</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'; font-size: 10pt;">)</div>
        </td>

  </tr>


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

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">Total revenue for the three months ended&#160;March 31, 2023 was $130.5 million compared to $141.9 million for the same period in 2022 and
    was comprised of the following (in millions):</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; 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'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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'; font-size: 10pt; font-weight: bold;">2023</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'; font-size: 10pt; font-weight: bold;">2022</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'; 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'; 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'; 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'; 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'; font-size: 10pt;">50.2</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'; 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'; font-size: 10pt;">53.8</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%;">
          <div style="text-align: left; text-indent: -27pt; margin-left: 45pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">6.5</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'; font-size: 10pt;">6.2</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%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -27pt; margin-left: 45pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;">12.3</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%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 45pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">67.7</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'; font-size: 10pt;">72.3</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: -9pt; margin-left: 18pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;">15.6</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">&#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'; font-size: 10pt;">17.4</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; margin-left: 18pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">22.5</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'; font-size: 10pt;">27.2</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; margin-left: 18pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;">2.0</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'; 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'; font-size: 10pt;">0.3</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>

    <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'; font-size: 10pt;">3.1</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'; font-size: 10pt;">Collaborative agreement 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'; font-size: 10pt;">38.4</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'; font-size: 10pt;">49.7</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: 45pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Eplontersen joint development 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'; font-size: 10pt;">24.4</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>

    <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'; font-size: 10pt;">19.9</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: 27pt; margin-left: 45pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">62.8</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'; font-size: 10pt;">69.6</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: 36pt; margin-left: 81pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;">130.5</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'; 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'; font-size: 10pt;">141.9</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 class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
    <div class="BRPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">22</div>

    </div>

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

    <div class="BRPFPageHeader">
      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We continued to derive our revenue for the first quarter of 2023 from diverse sources, with approximately half of our revenue coming
    from commercial products and half from numerous partnered programs. Commercial revenue for the first quarter of 2023 included $50 million from SPINRAZA royalties. Global SPINRAZA product sales of $443 million decreased six percent in the first quarter
    of 2023 compared to the same period in 2022 primarily due to the impact from foreign currency, fewer new patient starts in the U.S. and channel dynamics.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">R&amp;D revenue for the first quarter of 2023 included $24 million from AstraZeneca for its share of the global Phase 3 development
    costs for eplontersen, $20 million from Biogen for advancing several neurology disease programs and $15 million from GSK for advancing bepirovirsen into Phase 3 development.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Already in the second quarter of 2023, we have earned a $16 million milestone payment when QALSODY was approved in the U.S.</div>

  <div><br />
  </div>

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

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Our financial results for the three months ended March 31, 2023 and 2022 reflected the cost-sharing provisions related to our
    collaboration with AstraZeneca to develop and commercialize eplontersen for the treatment of ATTR. Under the terms of the collaboration agreement, AstraZeneca is currently paying 55 percent of the costs associated with the ongoing global Phase 3
    development program. Because we are leading and conducting the Phase 3 development program, we are recognizing as R&amp;D revenue the 55 percent of cost-share funding AstraZeneca is responsible for, net of our share of AstraZeneca's development
    expenses, in the same period we incur the related development expenses. In the first quarter of 2023, we earned $24 million in joint development revenue and recorded $47 million of R&amp;D expenses related to Phase 3 development expenses under this
    collaboration. In the first quarter of 2022, we earned $20 million in joint development revenue and recorded $36 million of R&amp;D expenses related to Phase 3 development expenses under this collaboration.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">As AstraZeneca is responsible for the majority of the medical affairs and commercial costs in the U.S. and all costs associated with
    bringing eplontersen to market outside the U.S., we are recognizing cost-share funding we receive from AstraZeneca related to these activities as a reduction of our medical affairs and commercialization expenses, which we classify as R&amp;D and
    selling, general and administrative, or SG&amp;A expenses, respectively. In the first quarter of 2023, we recognized $0.7 million and $1.3 million of medical affairs expenses and commercialization expenses for eplontersen, respectively, net of
    cost-share funding from AstraZeneca. In the first quarter of 2022, we recognized $0.4 million and $0.2 million of medical affairs expenses and commercialization expenses for eplontersen, respectively, net of cost-share funding from AstraZeneca. We
    expect our medical affairs and commercialization expenses to increase as eplontersen advances toward the market under our collaboration with AstraZeneca.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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'; 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', Times, serif; 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'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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'; font-size: 10pt; font-weight: bold;">2023</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'; font-size: 10pt; font-weight: bold;">2022</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'; 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'; 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'; font-size: 10pt;">217.7</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'; 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'; font-size: 10pt;">173.1</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%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">27.0</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <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'; font-size: 10pt;">26.3</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%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total operating 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'; 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'; font-size: 10pt;">244.7</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'; 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'; font-size: 10pt;">199.4</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; font-family: 'Times New Roman'; font-size: 10pt;">Operating expenses, excluding non-cash compensation expense related to equity awards, for the three months ended&#160;March 31, 2023 increased compared to the same period in 2022. Our R&amp;D expenses increased as we advanced our pipeline, which included an increase in the costs associated with our clinical studies as most of
    our Phase 3 studies were either fully enrolled or approaching full enrollment at the end of March 2023. Our SG&amp;A expenses increased due to expenses related to our go-to-market activities for eplontersen, olezarsen and donidalorsen. We expect our
    operating expenses, excluding <span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">non-cash compensation expense related to equity awards,</span> to continue to increase during the remainder of 2023 as we continue to advance
    our late-stage medicines in development and prepare for commercialization.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">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 class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
    <div class="BRPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">23</div>

    </div>

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

    <div class="BRPFPageHeader">
      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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', Times, serif; 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'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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'; font-size: 10pt; font-weight: bold;">2023</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'; font-size: 10pt; font-weight: bold;">2022</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'; 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'; 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'; font-size: 10pt;">1.2</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'; 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'; font-size: 10pt;">4.0</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'; 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'; 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'; 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%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;">1.3</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'; 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'; font-size: 10pt;">4.2</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'; 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'; font-size: 10pt;">Our research, development and patent expenses consist of expenses for drug discovery, 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'; 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', Times, serif; 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'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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'; font-size: 10pt; font-weight: bold;">2023</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'; font-size: 10pt; font-weight: bold;">2022</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'; 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'; 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'; font-size: 10pt;">178.2</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'; 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'; font-size: 10pt;">142.0</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'; 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'; font-size: 10pt;">19.6</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <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'; font-size: 10pt;">19.1</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'; 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'; 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'; font-size: 10pt;">197.8</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'; 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'; font-size: 10pt;">161.1</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'; font-size: 10pt;"><span style="text-decoration: underline;">Drug Discovery</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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 drug discovery research, and that of our partners. Drug discovery is also the function that is responsible for advancing our core technology. This function is also responsible for making
    investments in complementary technologies to expand the reach of our technologies.</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Our drug discovery expenses were as follows (in millions):</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; 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'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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'; font-size: 10pt; font-weight: bold;">2023</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'; font-size: 10pt; font-weight: bold;">2022</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'; font-size: 10pt;">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'; 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'; font-size: 10pt;">24.6</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'; 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'; font-size: 10pt;">19.1</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%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">3.9</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'; font-size: 10pt;">4.1</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'; font-size: 10pt;">Total 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'; 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'; font-size: 10pt;">28.5</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'; 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'; font-size: 10pt;">23.2</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'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">Drug discovery expenses</span>, excluding non-cash compensation expense
    related to equity awards,<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> increased in the </span>three months ended<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">&#160;</span>March 31, 2023<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> compared to the same period in </span>2022<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> as we continued to advance our research programs.</span></div>

  <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
    <div class="BRPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">24</div>

    </div>

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

    <div class="BRPFPageHeader">
      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><span style="text-decoration: underline;">Drug Development</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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', Times, serif; 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'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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'; font-size: 10pt; font-weight: bold;">2023</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'; font-size: 10pt; font-weight: bold;">2022</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; color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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'; 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'; font-size: 10pt;">2.1</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'; 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'; font-size: 10pt;">37.0</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'; font-size: 10pt;">27.0</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'; 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'; font-size: 10pt;">26.8</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'; font-size: 10pt;">8.7</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'; 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'; font-size: 10pt;">5.3</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'; font-size: 10pt;">1.7</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: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">2.3</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'; font-size: 10pt;">1.7</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'; 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'; font-size: 10pt;">19.1</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'; font-size: 10pt;">29.5</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'; font-size: 10pt;">Development overhead 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'; font-size: 10pt;">25.1</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'; font-size: 10pt;">19.3</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%;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total drug development 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'; font-size: 10pt;">115.6</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">&#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'; font-size: 10pt;">90.0</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: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">8.8</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'; font-size: 10pt;">8.6</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'; font-size: 10pt;">Total drug development 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'; 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'; font-size: 10pt;">124.4</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'; 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'; font-size: 10pt;">98.6</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


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

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">Our development expenses</span>, excluding non-cash compensation expense
    related to equity awards,<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> increased for the </span>three months ended<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">&#160;</span>March 31, 2023<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> compared to the same period in </span>2022<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> primarily due to our advancing late-stage pipeline and full or nearly full enrollment of multiple Phase 3 studies.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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. Because we always have numerous
    medicines in preclinical and varying stages of 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: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><span style="text-decoration: underline;">Medical Affairs</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Our medical affairs function is responsible for communicating scientific and clinical information to healthcare providers, medical
    professionals and patients.</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Our medical affairs expenses were as follows (in millions):</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; 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'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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'; font-size: 10pt; font-weight: bold;">2023</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'; font-size: 10pt; font-weight: bold;">2022</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'; font-size: 10pt;">Medical affairs 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'; 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'; font-size: 10pt;">4.3</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">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">2.8</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'; 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'; font-size: 10pt;">1.0</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <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'; font-size: 10pt;">0.3</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%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total medical affairs 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'; 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'; font-size: 10pt;">5.3</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'; 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'; font-size: 10pt;">3.1</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: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">Medical affairs expenses</span>, excluding non-cash compensation expense
    related to equity awards, increased in the three months ended&#160;March 31, 2023 compared to the same period in 2022. We expect medical <span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">affairs expenses</span>, excluding non-cash
    compensation expense related to equity awards, to increase in the remainder of 2023 as we advance our late-stage pipeline.</div>

  <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
    <div class="BRPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">25</div>

    </div>

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

    <div class="BRPFPageHeader">
      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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', Times, serif; 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'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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'; font-size: 10pt; font-weight: bold;">2023</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'; font-size: 10pt; font-weight: bold;">2022</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'; 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'; 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'; 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>

    <td valign="bottom" style="vertical-align: bottom; width: 1%; 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'; 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'; font-size: 10pt;">16.3</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;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">2.1</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'; font-size: 10pt;">2.7</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'; 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'; 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'; font-size: 10pt;">16.8</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'; 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'; font-size: 10pt;">19.0</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>

  </tr>


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

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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'; 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, information technology costs, procurement costs and waste disposal costs. We call these costs R&amp;D support expenses.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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', Times, serif; 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'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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'; font-size: 10pt; font-weight: bold;">2023</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'; font-size: 10pt; font-weight: bold;">2022</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'; 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'; 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'; font-size: 10pt;">6.5</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'; 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'; font-size: 10pt;">5.1</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'; 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'; 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'; font-size: 10pt;">4.0</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'; 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'; font-size: 10pt;">1.1</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">&#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'; font-size: 10pt;">0.7</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'; 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'; font-size: 10pt;">0.9</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'; font-size: 10pt;">0.9</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'; 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'; font-size: 10pt;">0.6</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">&#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'; font-size: 10pt;">0.6</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%; padding-bottom: 2px;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">2.6</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <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'; font-size: 10pt;">2.5</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%; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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%; background-color: #CCEEFF;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; 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'; font-size: 10pt;">19.0</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'; font-size: 10pt;">13.8</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'; 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'; font-size: 10pt;">3.8</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'; font-size: 10pt;">3.4</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

  </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'; font-size: 10pt;">Total R&amp;D support 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'; 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'; font-size: 10pt;">22.8</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'; 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'; font-size: 10pt;">17.2</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'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">R&amp;D support expenses</span>, excluding non-cash compensation expense
    related to equity awards,<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> increased in the </span>three months ended<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">&#160;</span>March 31, 2023<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> compared to the same period in </span>2022<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">. The increase was primarily related to increased occupancy and personnel costs to support advancing our pipeline and our technology. In October 2022, we executed a sale and leaseback transaction for our headquarters in Carlsbad,
      California. As a result, beginning in the fourth quarter of 2022, our occupancy costs increased because we began incurring rent expense for these facilities.</span></div>

  <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
    <div class="BRPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">26</div>

    </div>

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

    <div class="BRPFPageHeader">
      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">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'; 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', Times, serif; 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'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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'; font-size: 10pt; font-weight: bold;">2023</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'; font-size: 10pt; font-weight: bold;">2022</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'; 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'; 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'; font-size: 10pt;">38.2</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'; 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'; font-size: 10pt;">27.1</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%; padding-bottom: 2px;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">7.3</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; white-space: nowrap;" colspan="1">&#160;</td>

    <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'; font-size: 10pt;">7.0</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%; padding-bottom: 4px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;">45.5</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'; 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'; font-size: 10pt;">34.1</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: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">SG&amp;A expenses</span>, excluding non-cash compensation expense related
    to equity awards,<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> increased in the </span>three months ended<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">&#160;</span>March 31, 2023<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> compared to the same period in </span>2022 due to increased expenses related to our go-to-market
    activities for eplontersen, olezarsen and donidalorsen.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">Investment income for the three months ended&#160;March 31, 2023 was $18.6
    million compared to $2.0 million for the same period in 2022. Our investment income increased primarily due to an increase in interest rates associated with our investments in debt securities and an increase in our cash balance during the three months ended&#160;March 31, 2023 compared to
    the same period in 2022. Our cash balance increased due to the $500 million upfront payment we received in January 2023 from our royalty
    purchase agreement with Royalty Pharma Investments, or Royalty Pharma.</div>

  <div><br />
  </div>

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

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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', Times, serif; 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'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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'; font-size: 10pt; font-weight: bold;">2023</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'; font-size: 10pt; font-weight: bold;">2022</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'; font-size: 10pt;">Convertible 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'; font-size: 10pt;">Non-cash amortization of 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'; 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'; font-size: 10pt;">1.3</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">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">1.3</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'; 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'; font-size: 10pt;">0.2</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'; font-size: 10pt;">0.2</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%; padding-bottom: 2px; background-color: #CCEEFF;">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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%; 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'; 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'; font-size: 10pt;">0.6</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'; font-size: 10pt;">Total interest expense</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'; 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'; font-size: 10pt;">1.6</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'; 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'; font-size: 10pt;">2.1</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; white-space: nowrap;" colspan="1">&#160;</td>

  </tr>


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

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic; font-weight: bold;">Interest Expense Related to Sale of Future Royalties</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">We recorded $15.5 million of interest expense related to the sale of
      future royalties in the </span>three months ended<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">&#160;</span>March 31, 2023<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> as a result of the Royalty Pharma transaction, in which we
      sold a minority interest in our future royalties to Royalty Pharma for a $500 million upfront payment and $625 million of potential future payments. Refer to </span>Part I, Item 1, Note 10, <span style="font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;">Liability Related to Sale of Future Royalties</span>, in the Notes to our condensed consolidated financial statements for further details.</div>

  <div><br />
  </div>

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

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We recorded a net loss on investments of $0.5
    million for the three months ended&#160;March 31, 2023 compared to $6.6 million for the same period in 2022 due to changes in the fair value of our investments in privately held and publicly traded biotechnology companies.</div>

  <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
    <div class="BRPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">27</div>

    </div>

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

    <div class="BRPFPageHeader">
      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

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

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Beginning in 2022, the Tax Cuts and Jobs Act of 2017, or TCJA, requires taxpayers to amortize research and development expenditures over
    five years pursuant to Internal Revenue Code, or IRC, Section 174. Additionally, we expect to reflect the royalty purchase agreement with Royalty Pharma as a taxable sale, requiring us to include the proceeds from the sale, net of currently deductible
    issuance costs, as taxable income in 2023.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We recorded income tax expense of $11.4
    million and $1.1 million for the three months ended March 31, 2023 and 2022, respectively. The increase in income tax expense for the three
    months ended March 31, 2023, compared to the same period in 2022, relates primarily to the impact of the Royalty Pharma transaction.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic; font-weight: bold;">Net Loss and Net Loss per Share</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">We had a net loss of $124.3 million for the three months ended<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">&#160;</span>March 31, 2023 compared to net loss of $65.2 million for the same
    period in 2022, which reflects the fluctuations discussed above. Our b<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">asic and diluted net loss per share for the </span>three months ended<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">&#160;</span>March 31, 2023<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> and </span>2022<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> was $</span>0.87<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> and $</span>0.46<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">, respectively.</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"><a id="Liquidity"><!--Anchor--></a>Liquidity and Capital Resources</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We have financed our operations primarily from research and development collaborative agreements. We also finance our operations from
    commercial revenue from SPINRAZA royalties and TEGSEDI and WAYLIVRA commercial revenue. From our inception through March 31, 2023, we have
    earned approximately $6.6 billion in revenue. We have also financed our operations through the sale of our equity securities, the issuance of
    long-term debt and the sale of future royalties. From the time we were founded through March 31, 2023, we have raised net proceeds of
    approximately $2.1 billion from the sale of our equity securities. Additionally, from our inception through March 31, 2023, we have borrowed approximately $2.1
    billion under long-term debt arrangements and received proceeds of $0.5 billion from the sale of future royalties to finance a portion of our operations.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">Our cash, cash equivalents and short-term investments, working capital
      and long-term obligations increased from December 31, 2022 to </span>March 31, 2023. As discussed above, in the first quarter of 2023, we
    received an upfront payment of $500 million when we entered into a royalty purchase agreement with Royalty Pharma and recorded a corresponding long-term liability related to the sale of future royalties.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">The following table summarizes our contractual obligations, excluding our liability related to the sale of future royalties, as of March 31, 2023. The table provides a breakdown of when obligations become due. We provide a more detailed description of the major components of our debt
    in the paragraphs following the table:</div>

  <div><br />
  </div>

  <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; 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'; 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; white-space: nowrap;" colspan="10">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Payments Due by Period (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'; 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; white-space: nowrap;" colspan="2">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Total</div>
        </td>

    <td valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;" 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'; 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;" 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'; 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'; 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'; 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'; 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'; 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'; 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'; 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'; 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'; 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'; 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>

    <td valign="bottom" style="vertical-align: bottom; width: 1%;" colspan="1">&#160;</td>

    <td valign="bottom" style="text-align: 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'; 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'; font-size: 10pt;">549.5</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'; font-size: 10pt;">Operating leases</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'; font-size: 10pt;">294.6</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">&#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'; font-size: 10pt;">20.1</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">&#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'; font-size: 10pt;">274.5</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'; font-size: 10pt;">Building mortgage payments (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'; font-size: 10pt;">10.6</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">&#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'; font-size: 10pt;">0.5</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'; font-size: 10pt;">10.1</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'; 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'; 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'; 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'; 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'; 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'; 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'; font-size: 10pt;">1,488.7</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'; 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'; font-size: 10pt;">21.4</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'; 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'; font-size: 10pt;">1,467.3</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; font-family: 'Times New Roman'; font-size: 10pt;">Our contractual obligations consist primarily of our convertible debt. In addition, we also have facility leases, a facility mortgage, equipment
    financing arrangements and other obligations. <span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">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></div>

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      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">28</div>

    </div>

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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic; font-weight: bold;">Convertible Debt and Call Spread</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">Refer to Part I, Item 1, Note 11, <span style="font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;">Convertible Debt</span>, in the
    Notes to our condensed consolidated financial statements for the significant terms of each convertible debt instrument.</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic; font-weight: bold;">Operating Facilities</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; 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 had 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 were only required to make interest payments. We began making principal payments in 2022. Our manufacturing facility mortgage matures in August 2027.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">In October 2022, we concurrently entered into two purchase and sale agreements with a real estate investor. Under the agreements, we sold and leased
    back the facilities at our headquarters location in Carlsbad, California and will sell, subject to meeting certain closing conditions, two lots of undeveloped land adjacent to our headquarters. We sold the facilities at our headquarters, which includes
    our primary R&amp;D facility, for a total purchase price of $263.4 million and we expect to receive total proceeds of $33.0 million upon the close of the sale of the two lots. We used a portion of the sale proceeds to extinguish our outstanding
    mortgage debt on our primary R&amp;D facility of $51.3 million.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic; font-weight: bold;">Operating Leases</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">Refer to our Leases accounting policy in Part IV, Item 15, Note 1 of our audited financial statements included in our Annual Report on Form 10-K for the
    year ended December 31, 2022 for further details on our operating leases.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic; font-weight: bold;">Liability Related to Sale of Future Royalties</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">Refer to Part I, Item 1, <span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">Note 10, </span><span style="font-family: 'Times New Roman'; font-size: 10pt; font-style: italic; color: #000000;">Liability Related to Sale of Future Royalties</span><span style="font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;">, </span>in the Notes to our condensed
    consolidated financial statements for further details on our royalty purchase agreement with Royalty Pharma.</div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">In addition to contractual obligations, we had outstanding purchase orders as of March 31, 2023 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'; 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>

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    <div class="BRPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">29</div>

    </div>

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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div style="text-align: left;"><a id="Item3MarketRisk"><!--Anchor--></a><span style="font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold; color: #000000;">ITEM 3.</span><span class="TRGRRTFtoHTMLTab" style="display: inline-block; text-indent: 0px; font-size: 1px; width: 72pt">&#160;</span><span style="font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold; color: #000000;">QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK</span></div>

  <div><br />
  </div>

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

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We are also exposed to changes in foreign currency exchange rates as we have foreign subsidiaries with functional currencies other than
    the U.S. dollar. We translate our subsidiaries&#8217; functional currencies into our reporting currency, the U.S. dollar. As a result, our financial position, results of operations and cash flows can be affected by market fluctuations in the foreign
    currencies to U.S. dollar exchange rate, which are difficult to predict. A hypothetical 10 percent change in foreign exchange rates during any of the periods presented would not have had a material impact on our condensed consolidated financial
    statements.</div>

  <div><br />
  </div>

  <div><a id="Item4Controls"><!--Anchor--></a></div>
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  <tr>

    <td style="width: 72pt; vertical-align: top;"><span style="font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold; color: #000000;">ITEM 4.</span></td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">CONTROLS AND PROCEDURES</div>
        </td>

  </tr>


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

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We maintain disclosure controls and procedures 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 design 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'; font-size: 10pt;">As of our most recently completed fiscal year and as of the end of the period covered by this Quarterly Report on Form 10-Q, we carried
    out an evaluation of the effectiveness of the design and operation of our disclosure controls and procedures, as defined in Rules 13a-15(e) and 15d-15(e) under the Securities Exchange Act of 1934, as amended, under the supervision 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 March 31, 2023. <span style="font-family: 'Times New Roman'; font-size: 10pt;">There have been no significant changes in our internal
      controls or in other factors that could significantly affect internal controls subsequent to</span>&#160;March 31, 2023.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We also performed an evaluation of any changes in our internal controls over financial reporting that occurred during our last
      fiscal quarter and that have materially affected, or are reasonably likely to materially affect, our internal controls over financial reporting. We conducted this evaluation under the supervision of and with the participation of our management,
      including our Chief Executive Officer and Chief Financial Officer. That evaluation did not identify any changes in our internal controls over financial reporting that occurred during our latest fiscal quarter and that have materially affected, or are
      reasonably likely to materially affect, our internal controls over financial reporting.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"><a id="PARTII"><!--Anchor--></a>PART II &#8212; OTHER INFORMATION</div>

  <div><br />
  </div>

  <div><a id="ITEM1"><!--Anchor--></a></div>
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  <tr>

    <td style="width: 72pt; vertical-align: top;"><span style="font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold; color: #000000;">ITEM 1.</span></td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">LEGAL PROCEEDINGS</div>
        </td>

  </tr>


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

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">For details of legal proceedings, refer to Part I, Item 1, Note 12, <span style="font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;">Legal
      Proceedings</span>, in the Notes to our condensed consolidated financial statements<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">.</span></div>

  <div><br />
  </div>

  <div><a id="ITEM1A"><!--Anchor--></a></div>
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  <tr>

    <td style="width: 72pt; vertical-align: top;"><span style="font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold; color: #000000;">ITEM 1A.</span></td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">RISK FACTORS</div>
        </td>

  </tr>


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

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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. We have marked with an asterisk those risk
    factors that reflect substantive changes from the risk factors included in our Annual Report on Form 10-K for the year ended December 31, 2022.</div>

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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

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

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">There are a number of risks related to our business and our securities. Some of the principal risks related to our business include the following:</div>

  <div><br />
  </div>

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


  <tr>

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

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: Calibri; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Our ability to generate substantial revenue from the sale of our medicines;</div>
        </td>

  </tr>


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


  <tr>

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

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: Calibri; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;">&#932;</span>he availability of adequate coverage and payment rates for our medicines;</div>
        </td>

  </tr>


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


  <tr>

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

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: Calibri; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

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

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: Calibri; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Our ability to successfully manufacture our medicines;</div>
        </td>

  </tr>


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


  <tr>

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

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: Calibri; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Our ability to successfully develop and obtain marketing approvals for our medicines;</div>
        </td>

  </tr>


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


  <tr>

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

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: Calibri; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Our ability to secure and maintain effective corporate partnerships;</div>
        </td>

  </tr>


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


  <tr>

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

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: Calibri; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Our ability to sustain cash flows and achieve consistent profitability;</div>
        </td>

  </tr>


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


  <tr>

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

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: Calibri; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Our ability to protect our intellectual property;</div>
        </td>

  </tr>


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


  <tr>

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

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: Calibri; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Our ability to maintain the effectiveness of our personnel;</div>
        </td>

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

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: Calibri; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">The impacts of the COVID-19 pandemic and ongoing war between Russia and Ukraine; and</div>
        </td>

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

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: Calibri; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">The other factors set forth below.</div>
        </td>

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  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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'; 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 our 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'; font-size: 10pt;">We currently rely on third parties for the commercialization of our marketed medicines, have limited experience as a company in
      commercializing medicines and 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. If we continue
      to 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'; font-size: 10pt; font-weight: bold;">If the market does not accept our medicines, including QALSODY, SPINRAZA, TEGSEDI, WAYLIVRA, eplontersen and our other 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'; 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'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; 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, 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 QALSODY, SPINRAZA, TEGSEDI, WAYLIVRA and eplontersen, 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>

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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">The degree of market acceptance for our medicines, including QALSODY, SPINRAZA, TEGSEDI, WAYLIVRA and eplontersen, and our medicines in
    development, depends upon a number of factors, including the:</div>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">receipt and scope of marketing authorizations;</div>
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    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">cost and effectiveness of our medicines compared to other available therapies;</div>
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    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">patient convenience of the dosing regimen for our medicines; and</div>
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    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">reimbursement policies of government and third-party payers.</div>
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  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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 of the medicines that we may develop.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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 competitors in the U.S. market for TEGSEDI are patisiran and vutrisiran, both marketed by Alnylam Pharmaceuticals, Inc. Neither patisiran nor vutrisiran has a
    boxed warning nor does either require use of a REMS program. Additionally, the product label for WAYLIVRA in the European Union, or 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 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: left; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; 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 </span><span style="font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold; color: #000000;">QALSODY</span><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">,</span><span style="font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"> SPINRAZA, TEGSEDI, WAYLIVRA and eplontersen, and our medicines in development, our revenue will be limited.*</span></div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; 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, <span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">QALSODY,</span> SPINRAZA, TEGSEDI, WAYLIVRA and eplontersen, 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. In addition, third-party payers may never consider our future products as cost-effective and 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'; 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, or ACA, 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 ACA, as well as efforts to repeal or replace certain aspects of the ACA. It is unclear how future litigation and healthcare reform measures will impact the ACA and our business.</div>

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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">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, increase competition, lower out-of-pocket drug costs for patients, and foster scientific innovation to promote better health care and improved health. In addition, the Inflation Reduction Act of 2022, or the
    IRA, among other things, allows the U.S. Department of Health and Human Services, or HHS, to negotiate the price of certain single-source drugs covered under Medicare and imposes rebates under Medicare Part B and Medicare Part D. In an effort to curb
    Medicare patients&#8217; out-of-pocket costs for prescription drugs, the Part D redesign legislation requires manufacturers to contribute to the catastrophic coverage phase for Part D drugs as discounts through a manufacturer discount program. Furthermore,
    any reduction in reimbursement from Medicare and other government programs may result in a similar reduction in payments from private payers. Our future product sales may be subject to additional discounts from list price in the form of rebates and
    discounts provided to 340B covered entities. Changes to the 340B program or to Medicare or Medicaid programs at the federal or state level, including outcomes of ongoing litigation in our industry, may impact our product prices and rebate liability.
    Further, in February 2023, in response to President Biden&#8217;s executive order released in October 2022, the Secretary of the U.S. Department of HHS selected three new models for testing by the Centers for Medicare &amp; Medicaid Services Innovation
    Center to help lower the high cost of drugs, promote accessibility to life-changing drug therapies and improve quality of care. It is unclear whether or how these selected models or similar policy initiatives will impact prescription drug pricing in
    the future.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">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, which would negatively affect the potential commercial success of our products, our
    revenue and our profits.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">If we or our partners fail to compete effectively, our medicines, including QALSODY, SPINRAZA, TEGSEDI, WAYLIVRA, and eplontersen, 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'; 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. In addition, other companies are engaged in developing RNA-targeted technology. Our competitors may succeed in developing medicines that are:</div>

  <div><br />
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    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">priced lower than our medicines;</div>
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    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">reimbursed more favorably by government and other third-party payers than our medicines;</div>
        </td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">safer than our medicines;</div>
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    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">more effective than our medicines; or</div>
        </td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">more convenient to use than 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'; font-size: 10pt;">These competitive developments could make our medicines, including QALSODY, SPINRAZA, TEGSEDI, WAYLIVRA and eplontersen, 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'; 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 some of 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 QALSODY, SPINRAZA, TEGSEDI, WAYLIVRA and eplontersen.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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 or more successfully commercialize their products.</div>

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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Onasemnogene abeparvovec and risdiplam compete with SPINRAZA;</div>
        </td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Patisiran, tafamidis, tafamidis meglumine and vutrisiran compete with TEGSEDI and could compete with eplontersen;</div>
        </td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">Acoramidis could compete with TEGSEDI and </span>eplontersen<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">;</span></div>
        </td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">ARO-APOC3, lomitapide and pegozafermin could compete with WAYLIVRA and olezarsen;</div>
        </td>

  </tr>


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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Lanadelumab-flyo, C1 esterase inhibitor, berotralstat, C1 esterase inhibitor subcutaneous, garadacimab, and NTLA-2002 could compete with donidalorsen;</div>
        </td>

  </tr>


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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Olpasiran and SLN360 could compete with pelacarsen; and</div>
        </td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">NI-204 could compete with QALSODY.</div>
        </td>

  </tr>


</table>
  <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; 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>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; 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'; 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'; 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 QALSODY, SPINRAZA, TEGSEDI, WAYLIVRA and eplontersen, and our medicines in development.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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>

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    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">in the U.S., TEGSEDI&#8217;s label contains a boxed warning for thrombocytopenia and glomerulonephritis;</div>
        </td>

  </tr>


</table>
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    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">TEGSEDI requires periodic blood and urine monitoring; and</div>
        </td>

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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">Prescription medicines may be promoted only for the approved indication(s) 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'; 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 authorities 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'; 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.</div>

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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; 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'; 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>

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    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">fund our development activities for SPINRAZA;</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'; font-size: 10pt;">seek and obtain regulatory approvals for SPINRAZA; and</div>
        </td>

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</table>
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    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">successfully commercialize SPINRAZA.</div>
        </td>

  </tr>


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

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We are relying on Biogen to obtain additional regulatory approvals for SPINRAZA, generate additional clinical data for SPINRAZA,
    manufacture, and continue to 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 continue to successfully commercialize SPINRAZA, or if Biogen&#8217;s efforts in any of these respects are ineffective, revenues for SPINRAZA would be negatively affected.</div>

  <div><br />
  </div>

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

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">We have entered into a collaborative arrangement with AstraZeneca to develop and commercialize eplontersen. Under the terms of the
    collaboration agreement, we 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, except for certain Latin American 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'; 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 />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">If we are not successful in expanding our manufacturing capabilities or 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'; font-size: 10pt;">To successfully commercialize any of our medicines, we need to optimize and manage large-scale commercial manufacturing capabilities
    either on a standalone basis or through a third-party manufacturer. As our drug development and commercial pipeline increases and matures, we will have a greater need for clinical trial and commercial manufacturing capacity. To that end, we have begun
    work on a new manufacturing facility in Oceanside, California that will expand our manufacturing infrastructure. We will incur substantial expenditures to build our new manufacturing facility and, following its completion, will likely need to hire and
    train additional staff to operate the facility. 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>

  <div><br />
  </div>

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

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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">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 QALSODY, SPINRAZA, TEGSEDI, WAYLIVRA and eplontersen, and our medicines in development, or could result in enforcement action after authorization that might
    limit the commercial success of our medicines, including QALSODY, SPINRAZA, TEGSEDI, WAYLIVRA and eplontersen, and our medicines in development.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">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 COVID-19 pandemic or the ongoing war between Russia and Ukraine, could limit the commercial success of our
    medicines.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; 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; margin-top: 5pt; margin-bottom: 5pt; font-family: 'Times New Roman'; 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'; 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: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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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</table>
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    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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>

  </tr>


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

  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; 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 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 adversely affect our business, prospects, financial condition and results of operations.</div>

  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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'; 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 could be time consuming
    and expensive and 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>

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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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>

  <div><br />
  </div>

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          <div style="color: #000000; font-family: 'Times New Roman'; 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: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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 the U.S.;</div>
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    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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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</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">Drug discovery and drug development have 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(s), 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'; 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'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; 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 QALSODY, bepirovirsen, donidalorsen, </span>eplontersen<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">, ION363, olezarsen and pelacarsen, 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'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; 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, in October 2021, Biogen reported that QALSODY (tofersen) did not meet the primary clinical endpoint in the Phase 3 VALOR study;
      however, trends favoring QALSODY 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 QALSODY, bepirovirsen, donidalorsen, </span>eplontersen<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">, ION363, olezarsen and pelacarsen.</span></div>

  <div><br />
  </div>

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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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>
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    <td style="width: 36pt;"></td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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: 36pt;"></td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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>
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    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: Calibri; font-size: 11pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">a clinical study site may deviate from the protocol for the study;</div>
        </td>

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  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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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</table>
  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">The 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'; font-size: 10pt;">In addition, our current medicines, including QALSODY, SPINRAZA, TEGSEDI, WAYLIVRA and eplontersen 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, 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 ATTRv-PN, respectively, or the commercial opportunity
    for WAYLIVRA or TEGSEDI.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Any failure or delay in our clinical studies, including the studies of QALSODY, bepirovirsen, donidalorsen, eplontersen, ION363,
    olezarsen and pelacarsen, could reduce the commercial potential or viability of our medicines.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">We depend on third parties to conduct 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">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, Medpace, Inc., Parexel International Corporation, Syneos Health, Inc. and
    Thermo Fisher Scientific Inc. for the clinical studies for our medicines, including QALSODY, donidalorsen, eplontersen, ION363, olezarsen and pelacarsen. 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, but we are responsible for ensuring that such investigators 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. For example, some of our key vendors are experiencing
    labor shortages, which could impact their ability to perform services for us for certain of our clinical trials. The failure of these third parties to carry out their obligations, including as a result of delays or disruptions caused by the COVID-19
    pandemic, or a termination of our relationship with such third parties, could delay or prevent the development, marketing authorization and commercialization of our medicines or additional marketing authorizations for TEGSEDI and WAYLIVRA.</div>

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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">In addition, while we do not have any clinical trial sites in Ukraine, we do have a limited number of clinical trial sites in Russia and
    surrounding countries that may be impacted by the ongoing war between Russia and Ukraine and could result in difficulties enrolling or completing our clinical trials in such areas on schedule. Furthermore, the U.S. and its European allies have imposed
    significant sanctions against Russia, including regional embargoes, full blocking sanctions, and other restrictions targeting major Russian financial institutions. The U.S. government has also indicated it will consider imposing additional sanctions
    and other similar measures in the future. Our ability to conduct clinical trials in Russia may become restricted under applicable sanctions laws, which would require us to identify alternative trial sites, and could increase our costs and delay the
    clinical development of certain of our medicines.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; 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'; 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 some 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'; font-size: 10pt;">Our corporate partners are developing and funding many of the medicines in our development pipeline. For example, we are relying on:</div>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Novartis for development and funding of pelacarsen;</div>
        </td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Biogen for development and funding of QALSODY;</div>
        </td>

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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Biogen for additional studies of SPINRAZA; and</div>
        </td>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">GSK for development and funding of bepirovirsen.</div>
        </td>

  </tr>


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

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">If any of these pharmaceutical companies stops developing and 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, in 2022, Pfizer and
    Bayer decided to discontinue the clinical development programs for vupanorsen and fesomersen, respectively.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">In addition to receiving funding, we enter into collaborative arrangements with third parties to:</div>

  <div><br />
  </div>

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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">conduct clinical studies;</div>
        </td>

  </tr>


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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">seek and obtain marketing authorizations; and</div>
        </td>

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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">manufacture and commercialize our medicines.</div>
        </td>

  </tr>


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

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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, Biogen, GSK, Novartis, and Roche, these collaborations may not continue or result in commercialized medicines, or may not progress as quickly as we anticipated.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">For example, a collaborator such as AstraZeneca, Biogen, GSK, Novartis, or Roche, could determine that it is in its financial interest
    to:</div>

  <div><br />
  </div>

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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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>

  </tr>


</table>
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  <tr>

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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">pursue higher-priority programs or change the focus of its own development programs; or</div>
        </td>

  </tr>


</table>
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  <tr>

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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">choose to devote fewer resources to our medicines than it does to its own medicines.</div>
        </td>

  </tr>


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

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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 QALSODY, SPINRAZA, bepirovirsen, eplontersen and pelacarsen.</div>

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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">We may not be able to benefit from orphan drug designation for our medicines.</div>

  <div style="text-align: justify; text-indent: 40.8pt; margin-top: 12pt; color: #000000; font-family: 'Times New Roman'; 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 and to ION582
    for the treatment of patients with Angelman syndrome. The FDA and EMA have granted orphan drug designation to TEGSEDI for the treatment of patients with ATTRv-PN, 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. If we lose orphan drug exclusivity on any of our medicines, we may face increased competition and lose market share for such
    medicine.</div>

  <div><br />
  </div>

  <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt; font-style: italic; font-weight: bold;">Risks related to our financial condition</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">Many of our medicines are undergoing clinical studies or are in the early stages of research and development. Most of our 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. In
    addition, as we commercialize more medicines on our own, we will need to invest significant financial resources to continue developing the infrastructure required to successfully commercialize our medicines, including the build-out of a new
    manufacturing facility. All of these activities will require significant cash. As of March 31, 2023, we had cash, cash equivalents and
    short-term investments equal to $2.3 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:</div>

  <div><br />
  </div>

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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">successful commercialization of SPINRAZA, TEGSEDI and WAYLIVRA;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">the profile and launch timing of our medicines, including QALSODY, bepirovirsen, donidalorsen, eplontersen, ION363, olezarsen and pelacarsen;</div>
        </td>

  </tr>


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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">changes in existing collaborative relationships and our ability to establish and maintain additional collaborative arrangements;</div>
        </td>

  </tr>


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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">continued scientific progress in our research, drug discovery and development programs;</div>
        </td>

  </tr>


</table>
  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">the size of our programs and progress with preclinical and clinical studies;</div>
        </td>

  </tr>


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


  <tr>

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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">the time and costs involved in obtaining marketing authorizations;</div>
        </td>

  </tr>


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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">competing technological and market developments, including the introduction by others of new therapies that address our markets; and</div>
        </td>

  </tr>


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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">our manufacturing requirements and capacity to fulfill such requirements.</div>
        </td>

  </tr>


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

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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 on
    acceptable terms or at all. 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>

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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">Because drug discovery and development require substantial lead-time and money prior to commercialization, our expenses have generally
    exceeded our revenue since we were founded in January 1989. As of March 31, 2023, we had an accumulated deficit of approximately $1.6 billion and stockholders&#8217; equity of approximately $0.5
    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 historically 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. We will now and continuing into the
    foreseeable future need to invest significant financial resources to develop capabilities to commercialize medicines on our own and expect that our income in the future will be driven primarily by commercial sales. If we do not earn substantial revenue
    from commercial sales, we may incur additional operating losses in the future, which could restrict our ability to successfully develop additional medicines or sustain future profitability.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">We may not be entitled to obtain additional milestone payments under our royalty monetization agreement with Royalty Pharma.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">In January 2023, we entered into a Royalty Purchase Agreement with Royalty Pharma Investments. In addition to the $500 million we
    received at closing, this agreement makes available to us up to an additional $625 million in milestone payments. However, these additional milestone payments are subject to satisfaction of certain conditions related to the regulatory approval or
    commercial sales of pelacarsen, in certain cases by specific deadlines. Should we not satisfy such conditions by the applicable deadlines, or if we fail to meet our obligations or default under this agreement, the actual amount of additional payments
    to us could be substantially less than the maximum amounts available thereunder.</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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, any of 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'; 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 <span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">QALSODY,</span> SPINRAZA, TEGSEDI, WAYLIVRA and eplontersen, 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'; font-size: 10pt;">If we or any licensor partner loses or cannot obtain patent protection for <span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">QALSODY,</span> SPINRAZA, TEGSEDI, WAYLIVRA or eplontersen, or any of our medicines in development, it could have a material adverse impact on our business.</div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; 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'; 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>

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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt; font-style: italic; font-weight: bold;">Risks related to product liability</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; 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>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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: left; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">We are dependent on the principal members of our management and
      scientific staff, and as we move towards commercializing medicines on our own, we will become increasingly dependent on the principal members of our commercial team. We do not have employment agreements with any of our employees that would prevent
      them from leaving us. The loss of our management, key scientific or commercial employees might slow the achievement of important research and development or commercial 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>

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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic; font-weight: bold;">Risks related to the COVID-19 pandemic and other events</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Our business may be adversely affected by pandemics, climate change, extreme weather events, earthquakes, war, civil or political
    unrest, terrorism or other catastrophic events.</div>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 40.5pt; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">Our business could be 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 disruption in the operations of third-party manufacturers and contract research organizations upon
      whom we rely. For example, some physician and hospital policies that were put in place as a result of the COVID-19 pandemic restricted in-person access by third parties, which in some cases impacted our commercialization efforts for TEGSEDI and
      WAYLIVRA. In addition, in December 2021, Novartis announced that enrollment for the Phase 3 HORIZON study had been delayed due to the COVID-19 pandemic.</span>&#160;<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">The
      COVID-19 pandemic continues to evolve, and while we believe we have not 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.</span></div>

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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

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  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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 currently manufacture most of our research and clinical supplies in a manufacturing
    facility located in Carlsbad, California and will move such manufacturing to our new facility in Oceanside, California once it is built. 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, 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>

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  <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic; font-weight: bold;">Risks related to cybersecurity</div>

  <div><br />
  </div>

  <div style="text-align: justify; font-family: 'Times New Roman'; 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; color: #000000; font-family: 'Times New Roman'; 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. In addition, the number and
    frequency of cybersecurity events globally may be heightened during times of geopolitical tension or instability between countries, including, for example, the ongoing war between Russia and Ukraine, as a result of which several companies (not
    including us) have reported recent cybersecurity events.</div>

  <div><br />
  </div>

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

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  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic; font-weight: bold;">Risks related to our securities and the global credit markets</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">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 impacts of the 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 QALSODY, SPINRAZA, TEGSEDI, WAYLIVRA, bepirovirsen, donidalorsen, eplontersen, ION363, olezarsen and pelacarsen, the price of our securities could decrease.</div>

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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; 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'; 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 March 31, 2023, the market price of our common stock ranged from $48.82 to $31.46 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>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Broad market factors may materially harm the market price of our common stock irrespective of our operating performance. For example,
    the COVID-19 pandemic, the ongoing war between Russia and Ukraine and measures taken in response thereto and the recent failure of Silicon Valley Bank caused significant disruptions of global financial markets and resulted in increased volatility in
    the trading price of our common stock. In addition, industry factors may materially harm the market price of our common stock. Nasdaq, and the market for biotechnology companies in particular, have historically 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 that 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.</div>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; 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 />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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>

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  </div>

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

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; 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-family: Times; 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.
      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-family: 'Times New Roman'; font-size: 10pt; 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>

  <div><br />
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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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>

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

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  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt; font-weight: bold;">Negative conditions in the global credit markets and financial services and other industries may adversely affect our business,
    financial condition or stock price.*</div>

  <div><br />
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  <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">The global credit and financial markets have experienced extreme
      volatility and disruptions recently, including as a result of the ongoing COVID-19 pandemic</span>&#160;<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">and war between Russia and Ukraine and measures taken in response
      thereto, and more recently, the failure of Silicon Valley Bank. These disruptions can result in severely diminished liquidity and credit availability, declines in consumer confidence, declines in economic growth, increases in unemployment rates and
      uncertainty about economic stability. There can be no assurance that further deterioration in credit and financial markets and confidence in economic conditions will not occur. If the current equity and credit markets deteriorate, it may make any
      necessary debt or equity financing more difficult, more costly and more dilutive. Failure to secure any necessary financing in a timely manner and on favorable terms could have a material adverse effect on our operations, growth plans, financial
      performance or stock price. In addition, 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. Furthermore, due to the rapidly rising inflation rate, we may experience significantly increased costs of goods and services for our business.</span></div>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman'; 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'; font-size: 10pt;">compliance with differing or unexpected regulatory requirements for our medicines and foreign employees;</div>
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          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">complexities associated with managing multiple payer reimbursement regimes, government payers or patient self-pay systems;</div>
        </td>

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          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">difficulties in staffing and managing foreign operations;</div>
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          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">in certain circumstances, increased dependence on the commercialization efforts and regulatory compliance of third-party distributors or strategic partners;</div>
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          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">foreign government taxes, regulations and permit requirements;</div>
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          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">U.S. and foreign government tariffs, trade restrictions, price and exchange controls and other regulatory requirements;</div>
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          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">anti-corruption laws, including the Foreign Corrupt Practices Act, or the FCPA, and its equivalent in foreign jurisdictions;</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'; font-size: 10pt;">economic weakness, including inflation, natural disasters, war, events of terrorism, political instability or public health issues or pandemics, such as the COVID-19
            pandemic, in particular foreign countries or globally;</div>
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    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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>

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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">compliance with tax, employment, privacy, immigration and labor laws, regulations and restrictions for employees living or traveling abroad;</div>
        </td>

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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">workforce uncertainty in countries where labor unrest is more common than in the U.S.; and</div>
        </td>

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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">changes in diplomatic and trade relationships.</div>
        </td>

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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

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

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic; font-weight: bold;">Risks related to compliance with laws</div>

  <div><br />
  </div>

  <div style="text-align: left; font-family: 'Times New Roman'; 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'; 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. 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>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; 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>

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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>

  <div><br />
  </div>

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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">interruption of our research, development and manufacturing efforts;</div>
        </td>

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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">injury to our employees and others;</div>
        </td>

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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">environmental damage resulting in costly clean up; and</div>
        </td>

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

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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>
        </td>

  </tr>


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

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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 for pollution liability in amounts and types that we consider commercially reasonable, 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>

  <div><br />
  </div>

  <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; 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 />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Each year we are required to evaluate our internal control systems 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'; 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. In July 2010, the Dodd-Frank Wall Street Reform and Protection Act, or the Dodd-Frank Act, was enacted, and in August 2022, the SEC adopted additional rules and regulations under the Dodd-Frank Act related to &#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 has and may in the future lead
    to additional compliance costs and impact the manner in which we operate our business.</div>

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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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 carry forward 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'; 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 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>

  <div><br />
  </div>

  <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman'; 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'; 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'; 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'; 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'; 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>

  <div><br />
  </div>

  <div><br />
  </div>

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      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

  <div><br />
  </div>

  <div><a id="ITEM2"><!--Anchor--></a></div>
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    <td style="width: 72pt; vertical-align: top;"><span style="font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold; color: #000000;">ITEM 2.</span></td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">UNREGISTERED SALES OF EQUITY SECURITIES AND USE OF PROCEEDS</div>
        </td>

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

  <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">Not applicable.</div>

  <div><br />
  </div>

  <div><a id="ITEM3"><!--Anchor--></a></div>
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    <td style="width: 72pt; vertical-align: top;"><span style="font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold; color: #000000;">ITEM 3.</span></td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">DEFAULT UPON SENIOR SECURITIES</div>
        </td>

  </tr>


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

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Not applicable.</div>

  <div><br />
  </div>

  <div><a id="ITEM4"><!--Anchor--></a></div>
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    <td style="width: 72pt; vertical-align: top;"><span style="font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold; color: #000000;">ITEM 4.</span></td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">MINE SAFETY DISCLOSURES</div>
        </td>

  </tr>


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

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Not applicable.</div>

  <div><br />
  </div>

  <div><a id="ITEM5"><!--Anchor--></a></div>
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    <td style="width: 72pt; vertical-align: top;"><span style="font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold; color: #000000;">ITEM 5.</span></td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">OTHER INFORMATION</div>
        </td>

  </tr>


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

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Not applicable.</div>

  <div><br />
  </div>

  <div style="text-align: left;"><a id="ITEM6"><!--Anchor--></a><span style="font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold; color: #000000;">ITEM 6.</span><span class="TRGRRTFtoHTMLTab" style="display: inline-block; text-indent: 0px; font-size: 1px; width: 72pt">&#160;</span><span style="font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold; color: #000000;">EXHIBITS</span></div>

  <div><br />
  </div>

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

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

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Exhibits</div>
        </td>

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

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    <td style="width: 8.46%; vertical-align: top; border-bottom: #000000 2px solid;">
          <div style="text-align: left; margin-left: 4.5pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Exhibit Number</div>
        </td>

    <td style="width: 1.5%; vertical-align: top;">&#160;</td>

    <td style="width: 90.04%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Description of Document</div>
        </td>

  </tr>

  <tr>

    <td style="width: 8.46%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 4.5pt; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="ex10-1.htm">10.1</a></div>
        </td>

    <td style="width: 1.5%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.04%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;">Second Amended Non-Employee Director Compensation Policy.</div>
        </td>

  </tr>

  <tr>

    <td style="width: 8.46%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.04%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 8.46%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 4.5pt; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="ex10-2.htm">10.2</a></div>
        </td>

    <td style="width: 1.5%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.04%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;">Ionis Pharmaceuticals, Inc. Amended and Restated 2002 Non-Employee Directors&#8217; Stock Option Plan, as amended on March 14, 2023.</div>
        </td>

  </tr>

  <tr>

    <td style="width: 8.46%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.04%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 8.46%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 4.5pt; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="ex10-3.htm">10.3</a></div>
        </td>

    <td style="width: 1.5%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.04%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;">Forms of Restricted Stock Unit Grant Notice and 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, as amended on March 14, 2023.</div>
        </td>

  </tr>

  <tr>

    <td style="width: 8.46%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.04%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 8.46%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 4.5pt; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="ex10-4.htm">10.4</a></div>
        </td>

    <td style="width: 1.5%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.04%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">HTT Research, Development, Option and License Agreement among the Registrant, F. Hoffmann-La Roche Ltd and Hoffmann-La Roche Inc., dated as of
            April. 8, 2013.</div>
        </td>

  </tr>

  <tr>

    <td style="width: 8.46%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.04%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 8.46%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 4.5pt; font-family: 'Times New Roman'; font-size: 10pt;">10.5</div>
        </td>

    <td style="width: 1.5%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.04%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="https://www.sec.gov/Archives/edgar/data/874015/000087401523000105/exhibit10-81.htm">Royalty
              Purchase Agreement by and between the Registrant, Akcea Therapeutics, Inc. and Royalty Pharma Investments 2019 ICAV dated as of January 9, 2023</a>. Filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended
            December 31, 2022 and incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential.</div>
        </td>

  </tr>

  <tr>

    <td style="width: 8.46%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.04%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 8.46%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 4.5pt; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="ex31-1.htm">31.1</a></div>
        </td>

    <td style="width: 1.5%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.04%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Certification by Chief Executive Officer pursuant to Rules 13a-14(a) and 15d-14(a) under the Securities Exchange Act of 1934, as amended.</div>
        </td>

  </tr>

  <tr>

    <td style="width: 8.46%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.04%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 8.46%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 4.5pt; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="ex31-2.htm">31.2</a></div>
        </td>

    <td style="width: 1.5%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.04%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Certification by Chief Financial Officer pursuant to Rules 13a-14(a) and 15d-14(a) under the Securities Exchange Act of 1934, as amended.</div>
        </td>

  </tr>

  <tr>

    <td style="width: 8.46%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.04%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 8.46%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 4.5pt; font-family: 'Times New Roman'; font-size: 10pt;"><a style="font-family: 'Times New Roman'; font-size: 10pt;" href="ex32-1.htm">32.1</a><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">*</span></div>
        </td>

    <td style="width: 1.5%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.04%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; 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>
        </td>

  </tr>

  <tr>

    <td style="width: 8.46%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.04%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 8.46%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 4.5pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">101</div>
        </td>

    <td style="width: 1.5%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.04%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">The following financial statements from the Ionis Pharmaceuticals, Inc. Quarterly Report on Form 10-Q for the quarter ended March 31, 2023, formatted in Inline Extensible Business Reporting Language (iXBRL): (i) condensed consolidated balance sheets, (ii) condensed
            consolidated statements of operations, (iii) condensed consolidated statements of comprehensive income (loss), (iv) condensed consolidated statements of stockholders&#8217; equity, (v) condensed consolidated statements of cash flows and (vi) notes to
            condensed consolidated financial statements (detail tagged).</div>
        </td>

  </tr>

  <tr>

    <td style="width: 8.46%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 1.5%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

    <td style="width: 90.04%; vertical-align: top; background-color: #FFFFFF;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 8.46%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: left; margin-left: 4.5pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">104</div>
        </td>

    <td style="width: 1.5%; vertical-align: top; background-color: #CCEEFF;">&#160;</td>

    <td style="width: 90.04%; vertical-align: top; background-color: #CCEEFF;">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Cover Page Interactive Data File (formatted in iXBRL and included in exhibit 101).</div>
        </td>

  </tr>


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

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


  <tr>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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
            section, nor shall it be deemed incorporated by reference into any filing under the Securities Act of 1933, as amended, or the Securities Exchange Act of 1934, as amended.</div>
        </td>

  </tr>


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

  <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
    <div class="BRPFPageFooter">
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">48</div>

    </div>

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

    <div class="BRPFPageHeader">
      <div style="text-align: left; color: #0000FF; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"><a style="font-family: 'Times New Roman'; font-size: 8pt;" href="#Index">Index</a></div>

    </div>

  </div>

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

  <div><br />
  </div>

  <div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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><br />
  </div>

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


  <tr>

    <td style="width: 27.57%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Signatures</div>
        </td>

    <td style="width: 2.19%; vertical-align: bottom;">&#160;</td>

    <td style="width: 50.36%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Title</div>
        </td>

    <td style="width: 2.15%; vertical-align: bottom;">&#160;</td>

    <td style="width: 17.72%; vertical-align: bottom; border-bottom: #000000 2px solid;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Date</div>
        </td>

  </tr>

  <tr>

    <td style="width: 27.57%; vertical-align: top;">&#160;</td>

    <td style="width: 2.19%; vertical-align: bottom;">&#160;</td>

    <td style="width: 50.36%; vertical-align: top;">&#160;</td>

    <td style="width: 2.15%; vertical-align: bottom;">&#160;</td>

    <td style="width: 17.72%; vertical-align: top;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 27.57%; vertical-align: top; border-bottom: #000000 2px solid;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">/s/ BRETT P. MONIA</div>
        </td>

    <td style="width: 2.19%; vertical-align: bottom;" rowspan="2">&#160;</td>

    <td style="width: 50.36%; vertical-align: top;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Director and Chief Executive Officer</div>
        </td>

    <td style="width: 2.15%; vertical-align: bottom;" rowspan="2">&#160;</td>

    <td style="width: 17.72%; vertical-align: bottom;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 27.57%; vertical-align: top;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Brett P. Monia, Ph.D.</div>
        </td>

    <td style="width: 50.36%; vertical-align: top;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(Principal executive officer)</div>
        </td>

    <td style="width: 17.72%; vertical-align: bottom;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">May 3, 2023</div>
        </td>

  </tr>

  <tr>

    <td style="width: 27.57%; vertical-align: top;">&#160;</td>

    <td style="width: 2.19%; vertical-align: bottom;">&#160;</td>

    <td style="width: 50.36%; vertical-align: top;">&#160;</td>

    <td style="width: 2.15%; vertical-align: bottom;">&#160;</td>

    <td style="width: 17.72%; vertical-align: bottom;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 27.57%; vertical-align: top; border-bottom: #000000 2px solid;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">/s/ ELIZABETH L. HOUGEN</div>
        </td>

    <td style="width: 2.19%; vertical-align: bottom;" rowspan="2">&#160;</td>

    <td style="width: 50.36%; vertical-align: top;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Executive Vice President, Finance and Chief Financial Officer</div>
        </td>

    <td style="width: 2.15%; vertical-align: bottom;" rowspan="2">&#160;</td>

    <td style="width: 17.72%; vertical-align: bottom;">&#160;</td>

  </tr>

  <tr>

    <td style="width: 27.57%; vertical-align: top;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Elizabeth L. Hougen</div>
        </td>

    <td style="width: 50.36%; vertical-align: top;">
          <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(Principal financial and accounting officer)</div>
        </td>

    <td style="width: 17.72%; vertical-align: bottom;">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">May 3, 2023</div>
        </td>

  </tr>


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<DOCUMENT>
<TYPE>EX-10.1
<SEQUENCE>2
<FILENAME>ex10-1.htm
<DESCRIPTION>EXHIBIT 10.1
<TEXT>
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    <div>
      <div style="text-align: right; color: #000000; font-weight: bold;">Exhibit 10.1</div>
      <div><br>
      </div>
      <div style="text-align: center; color: #000000; font-weight: bold;">Second Amended Non-Employee Director Compensation Policy</div>
      <div style="text-align: center; color: #000000; font-weight: bold;">As of April 24, 2023</div>
      <div><font style="font-size: 12pt; color: #000000;"> </font><br>
      </div>
      <div style="color: #000000;">Ionis Pharmaceuticals, Inc. (&#8220;<font style="font-weight: bold; font-style: italic;">Ionis</font>&#8221;) values the contributions made by its Board of Directors.&#160; In recognition of these valuable contributions, Ionis will
        provide each non-employee Director with the compensation described in this policy.</div>
      <div><font style="font-size: 12pt; color: #000000;"> </font><br>
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      <div style="color: #000000; font-weight: bold;"><u>Cash Compensation</u></div>
      <div>&#160;</div>
      <div style="color: #000000;">Each non-employee Director will receive cash compensation based on his or her role on the Board and Board committees as follows:</div>
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      <table cellspacing="0" cellpadding="0" border="0" class="cfttable" id="z1ff21439c9bf4edc9b66734914d878b2" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: rgb(0, 0, 0); width: 100%;">

          <tr>
            <td valign="bottom" style="vertical-align: top; border-color: rgb(0, 0, 0); border-style: solid; border-width: 2px;">
              <div style="text-align: center; font-weight: bold;">Role</div>
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              <div style="text-align: center; font-weight: bold;">Cash Compensation</div>
            </td>
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          <tr>
            <td valign="bottom" style="vertical-align: top; width: 88%; padding-bottom: 2px; border-left: #000000 solid 2px; border-right: #000000 solid 2px; background-color: #CCEEFF;">
              <div>Board Member (base retainer)</div>
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            <td valign="bottom" class="cftguttercell" colspan="1" style="text-align: right; vertical-align: bottom; width: 1%; background-color: rgb(204, 238, 255); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
            <td valign="bottom" class="cftcurrcell" colspan="1" style="vertical-align: bottom; width: 1%; border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
              <div>$</div>
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            <td valign="bottom" class="cftnumcell" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
              <div>60,000</div>
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            <td valign="bottom" nowrap="nowrap" class="cftfncell" colspan="1" style="vertical-align: bottom; width: 1%; border-right: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255); border-bottom: 2px solid rgb(0, 0, 0);">
              <div><sup style="font-weight: bold; vertical-align: text-top; line-height: 1; font-size: smaller;">(1)</sup>&#160;</div>
            </td>
          </tr>
          <tr>
            <td valign="bottom" style="vertical-align: top; width: 88%; padding-bottom: 2px; border-left: #000000 solid 2px; border-right: #000000 solid 2px;">
              <div>Non-Executive Chairman of the Board (additional)</div>
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            <td valign="bottom" class="cftguttercell" colspan="1" style="text-align: right; vertical-align: bottom; width: 1%; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
            <td valign="bottom" class="cftcurrcell" colspan="1" style="vertical-align: bottom; width: 1%; border-bottom: 2px solid rgb(0, 0, 0);">
              <div>$</div>
            </td>
            <td valign="bottom" class="cftnumcell" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: 2px solid rgb(0, 0, 0);">
              <div>40,000</div>
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            <td valign="bottom" nowrap="nowrap" class="cftfncell" colspan="1" style="vertical-align: bottom; width: 1%; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          </tr>
          <tr>
            <td valign="bottom" style="vertical-align: top; width: 88%; padding-bottom: 2px; border-left: #000000 solid 2px; border-right: #000000 solid 2px; background-color: #CCEEFF;">
              <div>Independent Lead Director (additional)</div>
            </td>
            <td valign="bottom" class="cftguttercell" colspan="1" style="text-align: right; vertical-align: bottom; width: 1%; background-color: rgb(204, 238, 255); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
            <td valign="bottom" class="cftcurrcell" colspan="1" style="vertical-align: bottom; width: 1%; border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
              <div>$</div>
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            <td valign="bottom" class="cftnumcell" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
              <div>40,000</div>
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          </tr>
          <tr>
            <td valign="bottom" style="vertical-align: top; width: 88%; border-left: #000000 solid 2px; border-right: #000000 solid 2px;">
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            <td valign="bottom" class="cftguttercell" colspan="1" style="text-align: right; vertical-align: bottom; width: 1%;">&#160;</td>
            <td valign="bottom" class="cftcurrcell" colspan="1" style="vertical-align: bottom; width: 1%;">&#160;</td>
            <td valign="bottom" class="cftnumcell" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;">&#160;</td>
            <td valign="bottom" nowrap="nowrap" class="cftfncell" colspan="1" style="vertical-align: bottom; width: 1%; border-right: #000000 solid 2px;">&#160;</td>
          </tr>
          <tr>
            <td valign="bottom" style="vertical-align: top; width: 88%; border-left: #000000 solid 2px; border-right: #000000 solid 2px; background-color: #CCEEFF;">
              <div style="margin-left: 9pt;">-Audit</div>
            </td>
            <td valign="bottom" class="cftguttercell" colspan="1" style="text-align: right; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
            <td valign="bottom" class="cftcurrcell" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
              <div>$</div>
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            <td valign="bottom" class="cftnumcell" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
              <div>24,000</div>
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            <td valign="bottom" nowrap="nowrap" class="cftfncell" colspan="1" style="vertical-align: bottom; width: 1%; border-right: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          </tr>
          <tr>
            <td valign="bottom" style="vertical-align: top; width: 88%; border-left: #000000 solid 2px; border-right: #000000 solid 2px;">
              <div style="margin-left: 9pt;">-Compliance</div>
            </td>
            <td valign="bottom" class="cftguttercell" colspan="1" style="text-align: right; vertical-align: bottom; width: 1%;">&#160;</td>
            <td valign="bottom" class="cftcurrcell" colspan="1" style="vertical-align: bottom; width: 1%;">
              <div>$</div>
            </td>
            <td valign="bottom" class="cftnumcell" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;">
              <div>20,000</div>
            </td>
            <td valign="bottom" nowrap="nowrap" class="cftfncell" colspan="1" style="vertical-align: bottom; width: 1%; border-right: #000000 solid 2px;">&#160;</td>
          </tr>
          <tr>
            <td valign="bottom" style="vertical-align: top; width: 88%; border-left: #000000 solid 2px; border-right: #000000 solid 2px; background-color: #CCEEFF;">
              <div style="margin-left: 9pt;">-Compensation</div>
            </td>
            <td valign="bottom" class="cftguttercell" colspan="1" style="text-align: right; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
            <td valign="bottom" class="cftcurrcell" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
              <div>$</div>
            </td>
            <td valign="bottom" class="cftnumcell" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
              <div>20,000</div>
            </td>
            <td valign="bottom" nowrap="nowrap" class="cftfncell" colspan="1" style="vertical-align: bottom; width: 1%; border-right: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          </tr>
          <tr>
            <td valign="bottom" style="vertical-align: top; width: 88%; border-left: #000000 solid 2px; border-right: #000000 solid 2px;">
              <div style="margin-left: 9pt;">-Finance</div>
            </td>
            <td valign="bottom" class="cftguttercell" colspan="1" style="text-align: right; vertical-align: bottom; width: 1%;">&#160;</td>
            <td valign="bottom" class="cftcurrcell" colspan="1" style="vertical-align: bottom; width: 1%;">
              <div>$</div>
            </td>
            <td valign="bottom" class="cftnumcell" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;">
              <div>20,000</div>
            </td>
            <td valign="bottom" nowrap="nowrap" class="cftfncell" colspan="1" style="vertical-align: bottom; width: 1%; border-right: #000000 solid 2px;">&#160;</td>
          </tr>
          <tr>
            <td valign="bottom" style="vertical-align: top; width: 88%; border-left: #000000 solid 2px; border-right: #000000 solid 2px; background-color: #CCEEFF;">
              <div style="margin-left: 9pt;">-Nominating, Governance and Review</div>
            </td>
            <td valign="bottom" class="cftguttercell" colspan="1" style="text-align: right; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
            <td valign="bottom" class="cftcurrcell" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
              <div>$</div>
            </td>
            <td valign="bottom" class="cftnumcell" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
              <div>20,000</div>
            </td>
            <td valign="bottom" nowrap="nowrap" class="cftfncell" colspan="1" style="vertical-align: bottom; width: 1%; border-right: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          </tr>
          <tr>
            <td valign="bottom" style="vertical-align: top; width: 88%; padding-bottom: 2px; border-left: #000000 solid 2px; border-right: #000000 solid 2px;">
              <div style="margin-left: 9pt;">-Science/Medical</div>
            </td>
            <td valign="bottom" class="cftguttercell" colspan="1" style="text-align: right; vertical-align: bottom; width: 1%; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
            <td valign="bottom" class="cftcurrcell" colspan="1" style="vertical-align: bottom; width: 1%; border-bottom: 2px solid rgb(0, 0, 0);">
              <div>$</div>
            </td>
            <td valign="bottom" class="cftnumcell" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: 2px solid rgb(0, 0, 0);">
              <div>20,000</div>
            </td>
            <td valign="bottom" nowrap="nowrap" class="cftfncell" colspan="1" style="vertical-align: bottom; width: 1%; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          </tr>
          <tr>
            <td valign="bottom" style="vertical-align: top; width: 88%; border-left: #000000 solid 2px; border-right: #000000 solid 2px; background-color: #CCEEFF;">
              <div>Committee Member (additional):</div>
            </td>
            <td valign="bottom" class="cftguttercell" colspan="1" style="text-align: right; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
            <td valign="bottom" class="cftcurrcell" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
            <td valign="bottom" class="cftnumcell" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
            <td valign="bottom" nowrap="nowrap" class="cftfncell" colspan="1" style="vertical-align: bottom; width: 1%; border-right: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          </tr>
          <tr>
            <td valign="bottom" style="vertical-align: top; width: 88%; border-left: #000000 solid 2px; border-right: #000000 solid 2px;">
              <div style="margin-left: 9pt;">-Audit</div>
            </td>
            <td valign="bottom" class="cftguttercell" colspan="1" style="text-align: right; vertical-align: bottom; width: 1%;">&#160;</td>
            <td valign="bottom" class="cftcurrcell" colspan="1" style="vertical-align: bottom; width: 1%;">
              <div>$</div>
            </td>
            <td valign="bottom" class="cftnumcell" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;">
              <div>12,000</div>
            </td>
            <td valign="bottom" nowrap="nowrap" class="cftfncell" colspan="1" style="vertical-align: bottom; width: 1%; border-right: #000000 solid 2px;">&#160;</td>
          </tr>
          <tr>
            <td valign="bottom" style="vertical-align: top; width: 88%; border-left: #000000 solid 2px; border-right: #000000 solid 2px; background-color: #CCEEFF;">
              <div style="margin-left: 9pt;">-Compliance</div>
            </td>
            <td valign="bottom" class="cftguttercell" colspan="1" style="text-align: right; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
            <td valign="bottom" class="cftcurrcell" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
              <div>$</div>
            </td>
            <td valign="bottom" class="cftnumcell" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
              <div>10,000</div>
            </td>
            <td valign="bottom" nowrap="nowrap" class="cftfncell" colspan="1" style="vertical-align: bottom; width: 1%; border-right: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          </tr>
          <tr>
            <td valign="bottom" style="vertical-align: top; width: 88%; border-left: #000000 solid 2px; border-right: #000000 solid 2px;">
              <div style="margin-left: 9pt;">-Compensation</div>
            </td>
            <td valign="bottom" class="cftguttercell" colspan="1" style="text-align: right; vertical-align: bottom; width: 1%;">&#160;</td>
            <td valign="bottom" class="cftcurrcell" colspan="1" style="vertical-align: bottom; width: 1%;">
              <div>$</div>
            </td>
            <td valign="bottom" class="cftnumcell" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;">
              <div>10,000</div>
            </td>
            <td valign="bottom" nowrap="nowrap" class="cftfncell" colspan="1" style="vertical-align: bottom; width: 1%; border-right: #000000 solid 2px;">&#160;</td>
          </tr>
          <tr>
            <td valign="bottom" style="vertical-align: top; width: 88%; border-left: #000000 solid 2px; border-right: #000000 solid 2px; background-color: #CCEEFF;">
              <div style="margin-left: 9pt;">-Finance</div>
            </td>
            <td valign="bottom" class="cftguttercell" colspan="1" style="text-align: right; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
            <td valign="bottom" class="cftcurrcell" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
              <div>$</div>
            </td>
            <td valign="bottom" class="cftnumcell" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
              <div>10,000</div>
            </td>
            <td valign="bottom" nowrap="nowrap" class="cftfncell" colspan="1" style="vertical-align: bottom; width: 1%; border-right: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          </tr>
          <tr>
            <td valign="bottom" style="vertical-align: top; width: 88%; border-left: #000000 solid 2px; border-right: #000000 solid 2px;">
              <div style="margin-left: 9pt;">-Nominating, Governance and Review</div>
            </td>
            <td valign="bottom" class="cftguttercell" colspan="1" style="text-align: right; vertical-align: bottom; width: 1%;">&#160;</td>
            <td valign="bottom" class="cftcurrcell" colspan="1" style="vertical-align: bottom; width: 1%;">
              <div>$</div>
            </td>
            <td valign="bottom" class="cftnumcell" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;">
              <div>10,000</div>
            </td>
            <td valign="bottom" nowrap="nowrap" class="cftfncell" colspan="1" style="vertical-align: bottom; width: 1%; border-right: #000000 solid 2px;">&#160;</td>
          </tr>
          <tr>
            <td valign="bottom" style="vertical-align: top; width: 88%; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255); border-bottom: 2px solid rgb(0, 0, 0);">
              <div style="margin-left: 9pt;">-Science/Medical</div>
            </td>
            <td valign="bottom" class="cftguttercell" colspan="1" style="text-align: right; vertical-align: bottom; width: 1%; background-color: rgb(204, 238, 255); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
            <td valign="bottom" class="cftcurrcell" colspan="1" style="vertical-align: bottom; width: 1%; border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
              <div>$</div>
            </td>
            <td valign="bottom" class="cftnumcell" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
              <div>10,000</div>
            </td>
            <td valign="bottom" nowrap="nowrap" class="cftfncell" colspan="1" style="vertical-align: bottom; width: 1%; border-right: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          </tr>

      </table>
      <div><font style="font-size: 12pt; color: #000000;"> </font><br>
      </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="z751a7b1731734dd6992c8745563d787c">

          <tr>
            <td style="width: 18pt;">&#160;</td>
            <td style="width: 18pt; vertical-align: top; color: rgb(0, 0, 0);">(1)</td>
            <td style="width: auto; vertical-align: top;">
              <div style="color: #000000;">Before March 31, 2024 this annual base cash retainer for each non-employee Director (not including fees for Non-Executive Chair, Independent Lead Director, Committee Chair or Committee Member) is limited to a
                maximum of $70,000 per year.</div>
            </td>
          </tr>

      </table>
      <div>&#160;</div>
      <div style="color: #000000; font-weight: bold;"><u>Equity Compensation</u></div>
      <div>&#160;</div>
      <div style="color: #000000;">Each non-employee Director will receive an initial stock option award and restricted stock unit award upon joining the Board and an annual stock option award and restricted stock unit award for each year of continued
        service as follows (subject to the aggregate grant date value limit described below):</div>
      <div><font style="font-size: 12pt; color: #000000;"> </font><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;" id="zb84d2ea5650f4aa2878e557ec33ca603">

          <tr>
            <td style="width: 62.48%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
              <div style="text-align: center; font-weight: bold;">Type of Grant</div>
            </td>
            <td style="width: 37.52%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
              <div style="text-align: center; font-weight: bold;">Number of Shares*</div>
            </td>
          </tr>
          <tr>
            <td style="width: 62.48%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
              <div>Initial Stock Option Grant</div>
            </td>
            <td style="width: 37.52%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
              <div style="text-align: center;">24,000</div>
            </td>
          </tr>
          <tr>
            <td style="width: 62.48%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
              <div>Initial Restricted Stock Unit Grant</div>
            </td>
            <td style="width: 37.52%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;">10,667</div>
            </td>
          </tr>
          <tr>
            <td style="width: 62.48%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
              <div>Annual Stock Option Grant</div>
            </td>
            <td style="width: 37.52%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
              <div style="text-align: center;">12,000</div>
            </td>
          </tr>
          <tr>
            <td style="width: 62.48%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
              <div>Annual Restricted Stock Unit Grant</div>
            </td>
            <td style="width: 37.52%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;">5,333</div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
        <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">1</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="color: #000000;">*These equity awards are to be automatically granted pursuant to the terms of the Ionis Pharmaceuticals, Inc.&#160;Amended and Restated 2002 Non-Employee Directors Stock Option Plan as approved by our stockholders on June 4,
        2020 (the <font style="font-weight: bold; font-style: italic;">&#8220;NED Plan&#8221;</font>).&#160; Notwithstanding the terms of the NED Plan, the following annual equity compensation limits will apply to all non-employee Directors through May 24, 2026: (1)
        incumbent non-employee Directors will receive no more than $450,000 in annual equity compensation per year based on the aggregate grant date fair value (as determined in accordance with FASB Topic ASC 718 or its successor), and (2) newly appointed
        non-employee Directors will receive no more than $675,000 in initial equity compensation based on the aggregate grant date fair value (as determined in accordance with FASB Topic ASC 718 or its successor).</div>
      <div><br>
      </div>
      <div style="color: #000000;">The exercise price of each stock option will be the Fair Market Value (as defined in the NED Plan) of Ionis&#8217; common stock on the date of grant.</div>
      <div><br>
      </div>
      <div>As set forth in the NED Plan, one-third of the shares subject to stock options or restricted stock units for initial grants to new non-employee Directors vest on each annual anniversary of the date of grant and annual grants <font style="color: #000000;">vest on either (1) the annual anniversary of the date of grant, or (2) the next regularly scheduled annual meeting of stockholders, whichever occurs earlier.</font></div>
      <div><font style="font-size: 12pt; color: #000000;"> </font><br>
      </div>
      <div style="text-align: justify;">While serving on the Board, each non-employee Director may not sell Ionis shares obtained pursuant to vesting of restricted stock unit awards if selling such shares would reduce the shares owned by such non-employee
        Director (not including stock options or unvested restricted stock units) below an amount that is equal to five times his or her annual base cash retainer.</div>
      <div>&#160;</div>
      <div style="color: #000000; font-weight: bold;"><u>Review of Non-Employee Director Compensation Policy</u></div>
      <div><br>
      </div>
      <div style="color: #000000;">This policy will be reviewed annually by Ionis&#8217; Compensation Committee and Board of Directors.</div>
      <div><br>
      </div>
      <div style="color: #000000;">On at least an annual basis, Ionis will retain an independent consultant to (1) advise the Compensation Committee on recent developments and best practices concerning director compensation, and (2) compare Ionis&#8217; director
        compensation levels, policies, practices, and procedures to a set of peer companies selected by the Compensation Committee with input from the independent consultant.</div>
      <div><br>
      </div>
      <div style="color: #000000;">Ionis reserves the right to amend this compensation policy at any time so long as the issuance of the equity awards comply with the terms of the NED Plan or any successor thereto.</div>
      <div><br>
      </div>
      <div><br>
      </div>
      <div style="text-align: center;">&#160;<font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">2</font></div>
      <div>
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<DOCUMENT>
<TYPE>EX-10.2
<SEQUENCE>3
<FILENAME>ex10-2.htm
<DESCRIPTION>EXHIBIT 10.2
<TEXT>
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    <title></title>
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<body bgcolor="#ffffff" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000;">
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    <div>
      <div style="text-align: right; font-weight: bold;">Exhibit 10.2</div>
      <div>&#160;</div>
      <div style="text-align: center; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>
      <div>&#160;</div>
      <div style="text-align: center; font-variant: small-caps; font-weight: bold;">Amended and Restated</div>
      <div>&#160;</div>
      <div style="text-align: center; font-variant: small-caps; font-weight: bold;">2002 Non-Employee Directors&#8217; Stock Option Plan</div>
      <div>&#160;</div>
      <div style="text-align: center; font-variant: small-caps; font-weight: bold;">Adopted by the Board of Directors September 11, 2001</div>
      <div style="text-align: center; font-variant: small-caps; font-weight: bold;">Approved by Stockholders May 31, 2002</div>
      <div style="text-align: center; font-variant: small-caps; font-weight: bold;">Effective Date: May 31, 2002</div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-weight: bold; font-variant: small-caps;">Amended: April 20, 2006 </font><font style="font-variant: small-caps;">(A</font>mendment approved by Board on</div>
      <div style="text-align: center;">December 12, 2005 and April 20, 2006 and by the Stockholders on May 3, 2006)</div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-weight: bold; font-variant: small-caps;">Amended: June 5, 2008 </font><font style="font-variant: small-caps;">(A</font>mendment approved by Board on</div>
      <div style="text-align: center;">September 13, 2007 and February 22, 2008 and by the Stockholders on June 5, 2008)</div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-weight: bold; font-variant: small-caps;">Amended and Restated:&#160; June 2, 2010 </font><font style="font-variant: small-caps;">(A</font>mendment and Restatement approved by Board on</div>
      <div style="text-align: center;">February 26, 2010 and by the Stockholders on June 2, 2010)</div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-weight: bold; font-variant: small-caps;">Amended and Restated:&#160; June 7, 2012 </font><font style="font-variant: small-caps;">(</font>Amendment and Restatement approved by Board on</div>
      <div style="text-align: center;">March 27, 2012 and by the Stockholders on June 7, 2012)</div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-weight: bold; font-variant: small-caps;">Amended and Restated:&#160; June 10, 2014 </font><font style="font-variant: small-caps;">(</font>Amendment and Restatement approved by Board on</div>
      <div style="text-align: center;">February 11, 2014 and by the Stockholders on June 10, 2014)</div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-weight: bold; font-variant: small-caps;">Amended and Restated:&#160; June 30, 2015 </font><font style="font-variant: small-caps;">(</font>Amendment and Restatement approved by Board on</div>
      <div style="text-align: center;">March 20, 2015 and by the Stockholders on June 30, 2015)</div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-weight: bold; font-variant: small-caps;">Amended and Restated:&#160; June 4, 2020 </font><font style="font-variant: small-caps;">(</font>Amendment and Restatement approved by Board on</div>
      <div style="text-align: center;">March 24, 2020 and by the Stockholders on June 4, 2020)</div>
      <div><br>
      </div>
      <div style="text-align: center; font-variant: small-caps;">Amended: March 14, 2023</div>
      <div><br>
      </div>
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z49a1c1f9dde44ecfa45bf1e54922226a" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

            <tr style="vertical-align: top;">
              <td style="vertical-align: top; width: 36pt;">
                <div style="text-align: justify;"><font style="font-weight: bold; color: rgb(0, 0, 0);">1.</font></div>
              </td>
              <td style="align: left; vertical-align: top; width: auto;">
                <div style="text-align: justify;"><font style="font-weight: bold; font-variant: small-caps;">Purposes.</font></div>
              </td>
            </tr>

        </table>
      </div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160; &#160; <font style="font-weight: bold;">Amendment and Restatement.&#160; </font>This Plan was originally an amendment and restatement
        of the Ionis Pharmaceuticals, Inc. 1992 Non-Employee Directors&#8217; Stock Option Plan, and is an amendment of the Ionis Pharmaceuticals, Inc. 2002 Non-Employee Directors&#8217; Stock Option Plan, as amended and restated on June 4, 2020.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(b)</font>&#160;&#160;&#160;&#160;&#160;&#160; &#160;&#160; <font style="font-weight: bold;">Eligible Recipients.</font>&#160; The persons eligible to receive Stock Awards are the
        Non-Employee Directors 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);">(c)</font>&#160;&#160;&#160;&#160;&#160;&#160; &#160;&#160; <font style="font-weight: bold;">Available Stock Awards.</font>&#160; The purpose of the Plan is to provide a means by which
        Non-Employee Directors may be given an opportunity to benefit from increases in value of the Common Stock through the granting of Stock Awards.</div>
      <div>&#160;</div>
      <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
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      </div>
      <!--PROfilePageNumberReset%Num%2%%%-->
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(d)</font>&#160;&#160;&#160;&#160;&#160; &#160; <font style="font-weight: bold;">General Purpose.</font>&#160; The Company, by means of the Plan, seeks to retain the services of
        its Non-Employee Directors, to secure and retain the services of new Non-Employee Directors and to provide incentives for such persons to exert maximum efforts for the success of the Company and its Affiliates.</div>
      <div>&#160;</div>
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z4da12b0bfa0947b1a1946065c94bf318" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

            <tr style="vertical-align: top;">
              <td style="vertical-align: top; width: 36pt;">
                <div style="text-align: justify;"><font style="font-weight: bold; color: rgb(0, 0, 0);">2.</font></div>
              </td>
              <td style="align: left; vertical-align: top; width: auto;">
                <div style="text-align: justify;"><font style="font-weight: bold; font-variant: small-caps;">Definitions.</font></div>
              </td>
            </tr>

        </table>
      </div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold; font-style: italic;">&#8220;Affiliate&#8221;</font> means any parent corporation or subsidiary
        corporation of the Company, whether now or hereafter existing, as those terms are defined in Sections 424(e) and (f), respectively, of the Code.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><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; font-style: italic;">&#8220;Annual Grant&#8221;</font> means an Option and/or RSU Award granted
        annually to all Non-Employee Directors who meet the criteria specified in subsection 6(b) of the Plan.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><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-weight: bold; font-style: italic;">&#8220;Board&#8221;</font> means the Board of Directors 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);">(d)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold; font-style: italic;">&#8220;Capitalization Adjustment&#8221;</font> has the meaning ascribed to that
        term in Section 12(a).</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(e)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold; font-style: italic;">&#8220;Change in Control&#8221;</font> means the occurrence, in a single
        transaction or in a series of related transactions, of any one or more of the following events:</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(i)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;any Exchange Act Person becomes the Owner, directly or indirectly, of securities of the Company representing more than 50%
        of the combined voting power of the Company&#8217;s then outstanding securities other than by virtue of a merger, consolidation or similar transaction and other than by a purchase of securities directly from the Company;</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;">Notwithstanding the foregoing, a Change in Control shall not be deemed to occur solely because the level of Ownership held by any Exchange Act Person (the &#8220;Subject Person&#8221;) exceeds the percentage
        threshold specified above of the outstanding voting securities as a result of a repurchase or other acquisition of voting securities by the Company reducing the number of shares outstanding, <font style="font-style: italic;">provided</font> that
        if a Change in Control would occur (but for the operation of this sentence) as a result of the acquisition of voting securities by the Company, and after such share acquisition, the Subject Person becomes the Owner of any additional voting
        securities (other than through a purchase directly from the Company) that, assuming the repurchase or other acquisition had not occurred, increases the percentage of the then outstanding voting securities Owned by the Subject Person over the
        percentage threshold specified above, then a Change in Control shall be deemed to occur.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(ii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#160; there is consummated a merger, consolidation or similar transaction involving (directly or indirectly) the Company and,
        immediately after the consummation of such merger, consolidation or similar transaction, the stockholders of the Company immediately prior thereto do not Own, directly or indirectly, outstanding voting securities representing more than 50% of the
        combined outstanding voting power of the surviving Entity in such merger, consolidation or similar transaction or more than 50% of the combined outstanding voting power of the parent of the surviving Entity in such merger, consolidation or similar
        transaction;</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(iii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; the stockholders of the Company approve or the Board approves a plan of complete dissolution or liquidation of the
        Company, or a complete dissolution or liquidation of the Company shall otherwise occur;</div>
      <div>&#160;</div>
      <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div class="BRPFPageNumberArea" style="text-align: center;"><font style="font-size: 8pt; font-weight: normal; font-style: normal;">2</font></div>
        <div class="BRPFPageBreak" style="page-break-after: always;">
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      </div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(iv)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; there is consummated a sale, lease, license or other disposition of all or substantially all of the consolidated assets of
        the Company and its Subsidiaries, other than a sale, lease, license or other disposition of all or substantially all of the consolidated assets of the Company and its Subsidiaries to an Entity, more than 50% of the combined voting power of the
        voting securities of which are Owned by stockholders of the Company in substantially the same proportions as their Ownership of the Company immediately prior to such sale, lease, license or other disposition; or</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(v)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;individuals who, on the date this Plan is adopted by the Board, are members of the Board (the &#8220;Incumbent Board&#8221;) cease for
        any reason to constitute at least a majority of the members of the Board; (<font style="font-style: italic;">provided, however,</font> that if the appointment or election (or nomination for election) of any new Board member was approved or
        recommended by a majority vote of the members of the Incumbent Board then still in office, such new member shall, for purposes of this Plan, be considered as a member of the Incumbent Board).</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;">Notwithstanding the foregoing or any other provision of this Plan, the definition of Change in Control (or any analogous term) in an individual written agreement between the Company or any
        Affiliate and the Holder shall supersede the foregoing definition with respect to Stock Awards subject to such agreement (it being understood, however, that if no definition of Change in Control or any analogous term is set forth in such an
        individual written agreement, the foregoing definition shall apply).</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(f)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#160; <font style="font-weight: bold; font-style: italic;">&#8220;Code&#8221;</font> means the Internal Revenue Code of 1986, as amended.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(g)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold; font-style: italic;">&#8220;Common Stock&#8221;</font> means the common stock 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);">(h)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold; font-style: italic;">&#8220;Company&#8221;</font> means Ionis Pharmaceuticals, Inc., a Delaware
        corporation.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(i)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold; font-style: italic;">&#8220;Consultant&#8221;</font> means any person, including an advisor, (i)
        engaged by the Company or an Affiliate to render consulting or advisory services and who is compensated for such services or (ii) serving as a member of the Board of Directors of an Affiliate and who is compensated for such services.&#160; However, the
        term &#8220;Consultant&#8221; shall not include Directors who are not compensated by the Company for their services as Directors, and the payment of a director&#8217;s fee by the Company for services as a Director shall not cause a Director to be considered a
        &#8220;Consultant&#8221; for purposes of the Plan.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(j)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold; font-style: italic;">&#8220;Continuous Service&#8221;</font> means that the Holder&#8217;s service with the
        Company or an Affiliate, whether as an Employee, Director or Consultant, is not interrupted or terminated.&#160; A change in the capacity in which the Holder renders service to the Company or an Affiliate as an Employee, Consultant or Director or a
        change in the entity for which the Holder renders such service, provided that there is no interruption or termination of the Holder&#8217;s service with the Company or an Affiliate, shall not terminate a Holder&#8217;s Continuous Service.&#160; For example, a
        change in status from a Non-Employee Director of the Company to a Consultant of an Affiliate or an Employee of the Company shall not constitute an interruption of Continuous Service.&#160; The Board or the chief executive officer of the Company, in that
        party&#8217;s sole discretion, may determine whether Continuous Service shall be considered interrupted in the case of any leave of absence approved by that party, including sick leave, military leave or any other personal leave.</div>
      <div>&#160;</div>
      <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div class="BRPFPageNumberArea" style="text-align: center;"><font style="font-size: 8pt; font-weight: normal; font-style: normal;">3</font></div>
        <div class="BRPFPageBreak" style="page-break-after: always;">
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      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(k)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold; font-style: italic;">&#8220;Corporate Transaction&#8221;</font> means the occurrence, in a single
        transaction or in a series of related transactions, of any one or more of the following events:</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(i)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; a sale or other disposition of all or substantially all, as determined by the Board in its discretion, of the consolidated
        assets of the Company and its Subsidiaries;</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(ii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; a sale or other disposition of at least 90% of the outstanding securities 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);">&#160;(iii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; a merger, consolidation or similar transaction following which the Company is not the surviving corporation; or</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(iv)</font>&#160;&#160;&#160;&#160;&#160; a merger, consolidation or similar transaction following which the Company is the surviving corporation but the shares of
        Common Stock outstanding immediately preceding the merger, consolidation or similar transaction are converted or exchanged by virtue of the merger, consolidation or similar transaction into other property, whether in the form of securities, cash or
        otherwise.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(l)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#160; <font style="font-weight: bold; font-style: italic;">&#8220;Director&#8221;</font> means a member of the Board of Directors 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);">(m)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold; font-style: italic;">&#8220;Disability&#8221;</font> means the permanent and total disability of a
        person within the meaning of Section 22(e)(3) of the Code.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(n)</font>&#160;&#160;&#160;&#160;&#160;&#160; &#160;&#160; <font style="font-weight: bold; font-style: italic;">&#8220;Employee&#8221;</font> means any person employed by the Company or an
        Affiliate.&#160; Service as a Director or payment of a director&#8217;s fee by the Company or an Affiliate shall not be sufficient to constitute &#8220;employment&#8221; by the Company or an Affiliate.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(o)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold; font-style: italic;">&#8220;Entity&#8221;</font> means a corporation, partnership or other entity.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(p)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold; font-style: italic;">&#8220;Exchange Act&#8221;</font> means the Securities Exchange Act of 1934, as
        amended.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(q)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold; font-style: italic;">&#8220;Exchange Act Person&#8221;</font> means any natural person, Entity or
        &#8220;group&#8221; (within the meaning of Section 13(d) or 14(d) of the Exchange Act), except that &#8220;Exchange Act Person&#8221; shall not include (A) the Company or any Subsidiary of the Company, (B) any employee benefit plan of the Company or any Subsidiary of the
        Company or any trustee or other fiduciary holding securities under an employee benefit plan of the Company or any Subsidiary of the Company, (C) an underwriter temporarily holding securities pursuant to an offering of such securities, or (D) an
        Entity Owned, directly or indirectly, by the stockholders of the Company in substantially the same proportions as their Ownership of stock 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);">(r)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold; font-style: italic;">&#8220;Fair Market Value&#8221;</font> means, as of any date, the value of the
        Common Stock determined as follows:</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(i)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;If the Common Stock is listed on any established stock exchange or traded on the Nasdaq National Market or the Nasdaq
        SmallCap Market, the Fair Market Value of a share of Common Stock shall be the closing sales price for such stock (or the closing bid, if no sales were reported) as quoted on such exchange or market (or the exchange or market with the greatest
        volume of trading in the Common Stock) on the last market trading day prior to the day of determination, as reported in The Wall Street Journal or such other source as the Board deems reliable.</div>
      <div>&#160;</div>
      <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div class="BRPFPageNumberArea" style="text-align: center;"><font style="font-size: 8pt; font-weight: normal; font-style: normal;">4</font></div>
        <div class="BRPFPageBreak" 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; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(ii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; In the absence of such markets for the Common Stock, the Fair Market Value shall be determined in good faith by the Board.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(s)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold; font-style: italic; color: rgb(0, 0, 0);">&#8220;Holder&#8221;</font><font style="color: rgb(0, 0, 0);">
          means </font>a person to whom an Option or RSU Award is granted pursuant to the Plan or, if applicable, such other person who holds an outstanding Option or RSU Award.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(t)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#160; <font style="color: rgb(0, 0, 0);"><font style="font-weight: bold; font-style: italic;">&#8220;Initial Grant&#8221;</font> means an
          Option and/or RSU granted to a Non-Employee Director who meets the criteria specified in subsection 6(a) of the Plan.</font></div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(u)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold; font-style: italic;">&#8220;Non-Employee Director&#8221;</font> means a Director who is not an
        Employee.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(v)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold; font-style: italic;">&#8220;Nonstatutory Stock Option&#8221;</font> means an Option not intended to
        qualify as an incentive stock option within the meaning of Section 422 of the Code and the regulations promulgated thereunder.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(w)</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold; font-style: italic;">&#8220;Officer&#8221;</font> means a person who is an officer of the Company within
        the meaning of Section 16 of the Exchange Act and the rules and regulations promulgated thereunder.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(x)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold; font-style: italic;">&#8220;Option&#8221;</font> means a Nonstatutory Stock Option granted pursuant to
        the Plan.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(y)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold; font-style: italic;">&#8220;Option Agreement&#8221;</font> means a written agreement between the
        Company and a Holder evidencing the terms and conditions of an individual Option grant.&#160; Each Option Agreement shall be subject to the terms and conditions of the Plan.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(z)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold; font-style: italic;"> &#8220;Own,&#8221; &#8220;Owned,&#8221; &#8220;Owner,&#8221; &#8220;Ownership&#8221;</font><font style="font-weight: bold;">&#160; </font>A person or Entity shall be deemed to &#8220;Own,&#8221; to have &#8220;Owned,&#8221; to be the &#8220;Owner&#8221; of, or to have acquired &#8220;Ownership&#8221; of securities if such person or Entity, directly or indirectly, through any contract, arrangement, understanding,
        relationship or otherwise, has or shares voting power, which includes the power to vote or to direct the voting, with respect to such securities.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(aa)</font>&#160;&#160;&#160;&#160; <font style="font-weight: bold; font-style: italic;">&#8220;Plan&#8221;</font> means this Ionis Pharmaceuticals, Inc. 2002 Non-Employee
        Directors&#8217; Stock Option Plan, which is an amendment and restatement of the Ionis Pharmaceuticals, Inc. 1992 Non-Employee Directors&#8217; Stock Option Plan.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(bb)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold; font-style: italic;">&#8220;RSU Award&#8221;</font> means a right to receive shares of Common Stock
        which is granted pursuant to the terms and conditions of Section 8.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(cc)</font>&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold; font-style: italic;">&#8220;RSU Award Agreement&#8221;</font> means a written agreement between the
        Company and a holder of a RSU Award evidencing the terms and conditions of a RSU Award grant.&#160; Each RSU Award Agreement shall be subject to the terms and conditions of the Plan.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(dd)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold; font-style: italic;">&#8220;Rule 16b-3&#8221;</font> means Rule 16b-3 promulgated under the Exchange
        Act or any successor to Rule 16b-3, as 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);">(ee)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold; font-style: italic;">&#8220;Securities Act&#8221;</font> means the Securities Act of 1933, as amended.</div>
      <div>&#160;</div>
      <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div class="BRPFPageNumberArea" style="text-align: center;"><font style="font-size: 8pt; font-weight: normal; font-style: normal;">5</font></div>
        <div class="BRPFPageBreak" 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; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(ff)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold; font-style: italic;">&#8220;Stock Award&#8221;</font> means an Option or RSU Award, as applicable.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(gg)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold; font-style: italic;">&#8220;Subsidiary&#8221;</font> means, with respect to the Company, (i) any
        corporation of which more than 50% of the outstanding capital stock having ordinary voting power to elect a majority of the board of directors of such corporation (irrespective of whether, at the time, stock of any other class or classes of such
        corporation shall have or might have voting power by reason of the happening of any contingency) is at the time, directly or indirectly Owned by the Company, and (ii) any partnership in which the Company has a direct or indirect interest (whether
        in the form of voting or participation in profits or capital contribution) of more than 50%.</div>
      <div>&#160;</div>
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z16754d4cd09c43d5acfd12ea6d072151" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

            <tr style="vertical-align: top;">
              <td style="vertical-align: top; width: 36pt;">
                <div style="text-align: justify;"><font style="font-weight: bold; color: rgb(0, 0, 0);">3.</font></div>
              </td>
              <td style="align: left; vertical-align: top; width: auto;">
                <div style="text-align: justify;"><font style="font-weight: bold; font-variant: small-caps;">Administration.</font></div>
              </td>
            </tr>

        </table>
      </div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Administration by Board.</font>&#160; The Board shall administer the Plan.&#160; The Board may
        delegate administration of the Plan to a committee.&#160; If delegated to a committee, references to the Board will include a reference to the committee, as applicable.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><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;">Powers of Board.</font>&#160; The Board shall have the power, subject to, and within the
        limitations of, the express provisions of the Plan:</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(i)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#160; To determine the provisions of each Stock Award to the extent not specified 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);">&#160;(ii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; To construe and interpret the Plan and Stock Awards granted under it, and to establish, amend and revoke rules and
        regulations for its administration.&#160; The Board, in the exercise of this power, may correct any defect, omission or inconsistency in the Plan or in any Option Agreement or RSU Agreement, in a manner and to the extent it shall deem necessary or
        expedient to make the Plan fully effective.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(iii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; To amend the Plan or a Stock Award as provided in Section 13.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(iv)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; To terminate or suspend the Plan as provided in Section 14.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(v)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; Generally, to exercise such powers and to perform such acts as the Board deems necessary or expedient to promote the best
        interests of the Company and that are not in conflict with the provisions of the Plan.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><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-weight: bold;">Effect of Board&#8217;s Decision.</font>&#160; All determinations, interpretations and constructions
        made by the Board in good faith shall not be subject to review by any person and shall be final, binding and conclusive on all persons.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(d)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Arbitration.&#160; </font>Any dispute or claim concerning any Stock Award granted (or not
        granted) pursuant to the Plan or any disputes or claims relating to or arising out of the Plan shall be fully, finally and exclusively resolved by binding arbitration conducted pursuant to the Commercial Arbitration Rules of the American
        Arbitration Association in San Diego, California.&#160; The Company shall pay all arbitration fees.&#160; In addition to any other relief, the arbitrator may award to the prevailing party recovery of its attorney&#8217;s fees and costs.&#160; By accepting a Stock
        Award, Holders and the Company waive their respective rights to have any such disputes or claims tried by a judge or jury.</div>
      <div>&#160;</div>
      <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div class="BRPFPageNumberArea" style="text-align: center;"><font style="font-size: 8pt; font-weight: normal; font-style: normal;">6</font></div>
        <div class="BRPFPageBreak" 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>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zf786b909fca54f898b51597bc4c00d1a" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

            <tr style="vertical-align: top;">
              <td style="vertical-align: top; width: 36pt;">
                <div style="text-align: justify;"><font style="font-weight: bold; color: rgb(0, 0, 0);">4.</font></div>
              </td>
              <td style="align: left; vertical-align: top; width: auto;">
                <div style="text-align: justify;"><font style="font-weight: bold; font-variant: small-caps;">Shares Subject to the Plan.</font></div>
              </td>
            </tr>

        </table>
      </div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160; &#160;&#160; <font style="font-weight: bold;">Share Reserve.</font>&#160; Subject to the provisions of Section 12(a) relating to
        Capitalization Adjustments, the Common Stock that may be issued pursuant to Stock Awards shall not exceed in the aggregate <font style="font-weight: bold;">2,800,000</font> shares of Common Stock.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(b)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Reversion of Shares to the Share Reserve.</font>&#160; If any Stock Award shall for any reason
        expire or otherwise terminate, in whole or in part, without having been exercised or vested in full, the shares of Common Stock not issued under such Stock Award shall revert to and again become available for issuance under the Plan.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><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-weight: bold;">Source of Shares.</font>&#160; The shares of Common Stock subject to the Plan may be unissued
        shares or reacquired shares, bought on the market or otherwise.</div>
      <div>&#160;</div>
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z7445d4bfafc44caf9ee0d54894556003" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

            <tr style="vertical-align: top;">
              <td style="vertical-align: top; width: 36pt;">
                <div style="text-align: justify;"><font style="font-weight: bold; color: rgb(0, 0, 0);">5.</font></div>
              </td>
              <td style="align: left; vertical-align: top; width: auto;">
                <div style="text-align: justify;"><font style="font-weight: bold; font-variant: small-caps;">Eligibility.</font></div>
              </td>
            </tr>

        </table>
      </div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;">The Stock Awards as set forth in Section 6 of the Plan automatically shall be granted under the Plan to all Non-Employee Directors.</div>
      <div>&#160;</div>
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z387f6ef8a31a4dbe8cc5c5949c2642c9" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

            <tr style="vertical-align: top;">
              <td style="vertical-align: top; width: 36pt;">
                <div style="text-align: justify;"><font style="font-weight: bold; color: rgb(0, 0, 0);">6.</font></div>
              </td>
              <td style="align: left; vertical-align: top; width: auto;">
                <div style="text-align: justify;"><font style="font-weight: bold; font-variant: small-caps;">Non-Discretionary Grants.</font></div>
              </td>
            </tr>

        </table>
      </div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#160; <font style="font-weight: bold;">Initial Grants.&#160; </font>Without any further action of the Board, each person who is
        elected or appointed for the first time to be a Non-Employee Director shall automatically be granted, on the terms and conditions set forth herein, an Initial Grant of Option and RSU Awards as follows:</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(i)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; An Option to purchase 24,000 shares of Common Stock; and</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(ii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; An RSU Award of 10,667 RSUs.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(iii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; The grant date for such initial options will be the date the Non-Employee Director was elected or appointed by the Board
        or stockholders of the Company, as applicable.&#160; The grant date for such initial RSU Awards will be the 15<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">th</sup> of the month following the end of the quarter in which such
        Non-Employee Director was elected or appointed by the Board or stockholders of the Company, as applicable.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><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;">Annual Grants.&#160; </font>Without any further action of the Board, a Non-Employee Director
        shall be granted an Annual Grant as follows: On July 1 of each year, beginning on July 1, 2020, each person who is then a Non-Employee Director automatically shall be granted, on the terms and conditions set forth herein, an Annual Grant of Option
        and RSU Awards as follows:</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(i)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; An Option to purchase 12,000 shares of Common Stock; and</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(ii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; An RSU Award of 5,333 RSUs.</div>
      <div>&#160;</div>
      <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div class="BRPFPageNumberArea" style="text-align: center;"><font style="font-size: 8pt; font-weight: normal; font-style: normal;">7</font></div>
        <div class="BRPFPageBreak" 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>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zce9804e88bfb4612b8c470e7242c67c7" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

            <tr style="vertical-align: top;">
              <td style="vertical-align: top; width: 36pt;">
                <div style="text-align: justify;"><font style="font-weight: bold; color: rgb(0, 0, 0);">7.</font></div>
              </td>
              <td style="align: left; vertical-align: top; width: auto;">
                <div style="text-align: justify;"><font style="font-weight: bold; font-variant: small-caps;">Option Provisions.</font></div>
              </td>
            </tr>

        </table>
      </div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;">Each Option shall be in such form and shall contain such terms and conditions as the Board shall deem appropriate.&#160; Each Option shall include (through incorporation of provisions hereof by
        reference in the Option or otherwise) the substance of each of the following provisions:</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Term.</font>&#160; No Option shall be exercisable after the expiration of 10 years from the
        date it was granted.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(b)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Exercise Price.</font>&#160; The exercise price of each Option shall be 100% of the Fair Market
        Value of the Common Stock subject to the Option on the date the Option is granted.&#160; Notwithstanding the foregoing, an Option may be granted with an exercise price lower than that set forth in the preceding sentence if such Option is granted
        pursuant to an assumption or substitution for another option in a manner satisfying the provisions of Section 424(a) of the Code.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><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-weight: bold;">Consideration.</font>&#160; The purchase price of Common Stock acquired pursuant to the
        exercise of an Option shall be paid, to the extent permitted by applicable law, by any combination of the following methods of payment:</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(i)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#160; by cash, check, bank draft or money order payable to the Company; or</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(ii)</font>&#160;&#160;&#160;&#160;&#160;&#160; pursuant to a program developed under Regulation T as promulgated by the Federal Reserve Board that, prior to the issuance
        of the stock subject to the Option, results in either the receipt of cash (or check) by the Company or the receipt of irrevocable instructions to pay the aggregate exercise price to the Company from the sales proceeds.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(d)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Transferability.</font>&#160; An Option will not be transferable except as determined by the
        Board.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(e)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Exercise Schedule.</font>&#160; The Option shall be exercisable as the shares of Common Stock
        subject to the Option vest.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(f)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Vesting Schedule.</font>&#160; The Option shall vest and become exercisable as follows:</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(i)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="color: rgb(0, 0, 0);">Initial Grants: one-third of the shares subject to the Option shall vest on each annual
          anniversary of the date of grant, provided that the Holder has, during the entire year prior to each vesting date, continuously served as a Non-Employee Director or as an Employee of or Consultant to the Company or any Affiliate, whereupon such
          option shall become fully exercisable in accordance with its terms with respect to that portion of the shares represented by that installment.</font></div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(ii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; Annual Grants: <font style="color: rgb(0, 0, 0);">100% of the shares subject to the Option shall vest on (1) the annual
          anniversary of the date of grant, or (2) the next regularly scheduled annual meeting of stockholders, whichever occurs earlier, provided that the Holder has, during the entire period from the date of grant through such vesting date, continuously
          served as a Non-Employee Director or as an Employee of or Consultant to the Company or any Affiliate, whereupon such option shall become fully exercisable in accordance with its terms.</font></div>
      <div>&#160;</div>
      <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div class="BRPFPageNumberArea" style="text-align: center;"><font style="font-size: 8pt; font-weight: normal; font-style: normal;">8</font></div>
        <div class="BRPFPageBreak" 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; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(g)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#160;&#160; <font style="font-weight: bold;">Termination of Continuous Service.</font>&#160; In the event that an Holder&#8217;s Continuous
        Service terminates (other than upon the Holder&#8217;s death or Disability), the Holder may exercise his or her Option (to the extent that the Holder was entitled to exercise such Option as of the date of termination) but only within such period of time
        ending on the earlier of (i) the date 3 months following the termination of the Holder&#8217;s Continuous Service (or such longer or shorter period specified in the Option Agreement), or (ii) the expiration of the term of the Option as set forth in the
        Option Agreement.&#160; If, after termination, the Holder does not exercise his or her Option within the time specified in the Option Agreement, the Option shall terminate.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(h)</font>&#160;&#160;&#160;&#160;&#160; &#160; <font style="font-weight: bold;">Extension of Termination Date.</font>&#160; An Holder&#8217;s Option Agreement may also provide that
        if the exercise of the Option following the termination of the Holder&#8217;s Continuous Service (other than upon the Holder&#8217;s death or Disability) would be prohibited at any time solely because the issuance of shares of Common Stock would violate the
        registration requirements under the Securities Act, then the Option shall terminate on the earlier of (i) the expiration of the term of the Option set forth in subsection 7(a) or (ii) the expiration of a period of 3 months after the termination of
        the Holder&#8217;s Continuous Service during which the exercise of the Option would not be in violation of such registration requirements.&#160; <font style="color: rgb(0, 0, 0);">In addition, unless otherwise provided in an Holder&#8217;s Option Agreement, if the
          immediate sale of any Common Stock received upon exercise of an Option following the termination of the Holder&#8217;s Continuous Service would violate the Company&#8217;s insider trading policy, then the Option shall terminate on the earlier of (i) the
          expiration of a period equal to the applicable post-termination exercise period after the termination of the Holder&#8217;s Continuous Service during which the sale of Common Stock received upon exercise of the Option would not be in violation of the
          Company&#8217;s insider trading policy, or (ii) the expiration of the term of the Option as set forth in the applicable Option Agreement.</font></div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(i)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#160; <font style="font-weight: bold;">Disability of Holder.</font>&#160; In the event that an Holder&#8217;s Continuous Service
        terminates as a result of the Holder&#8217;s Disability, the Holder may exercise his or her Option (to the extent that the Holder was entitled to exercise such Option as of the date of termination), but only within such period of time ending on the
        earlier of (i) the date 12 months following such termination (or such longer or shorter period specified in the Option Agreement) or (ii) the expiration of the term of the Option as set forth in the Option Agreement.&#160; If, after termination, the
        Holder does not exercise his or her Option within the time specified herein, the Option shall terminate.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(j)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Death of Holder.</font>&#160; In the event that (i) an Holder&#8217;s Continuous Service terminates
        as a result of the Holder&#8217;s death or (ii) the Holder dies within the period (if any) specified in the Option Agreement after the termination of the Holder&#8217;s Continuous Service for a reason other than death, then the Option may be exercised (to the
        extent the Holder was entitled to exercise such Option as of the date of death) by the Holder&#8217;s estate, by a person who acquired the right to exercise the Option by bequest or inheritance or by a person designated to exercise the Option upon the
        Holder&#8217;s death pursuant to subsection 7(d), but only within the period ending on the earlier of (1) the date 18 months following the date of death (or such longer or shorter period specified in the Option Agreement) or (2) the expiration of the
        term of such Option as set forth in the Option Agreement.&#160; If, after death, the Option is not exercised within the time specified herein, the Option shall terminate.</div>
      <div>&#160;</div>
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zb88eedf7392b42e280311234df4d1507" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

            <tr style="vertical-align: top;">
              <td style="vertical-align: top; width: 36pt;">
                <div style="text-align: justify;"><font style="font-weight: bold; color: rgb(0, 0, 0);">8.</font></div>
              </td>
              <td style="align: left; vertical-align: top; width: auto;">
                <div style="text-align: justify;"><font style="font-weight: bold; font-variant: small-caps;">Restricted Stock Unit Provisions.</font></div>
              </td>
            </tr>

        </table>
      </div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;">Each Restricted Stock Unit Award Agreement shall be in such form and shall contain such terms and conditions as the Board shall deem appropriate.&#160; The terms and conditions of Restricted Stock Unit
        Award Agreements may change from time to time, and the terms and conditions of separate Restricted Stock Unit Award Agreements need not be identical; <font style="font-style: italic;">provided, however</font>, that each Restricted Stock Unit Award
        Agreement shall conform to (through incorporation of the provisions hereof by reference in the Agreement or otherwise) the substance of each of the following provisions:</div>
      <div>&#160;</div>
      <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div class="BRPFPageNumberArea" style="text-align: center;"><font style="font-size: 8pt; font-weight: normal; font-style: normal;">9</font></div>
        <div class="BRPFPageBreak" 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; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Consideration.</font>&#160; At the time of grant of a Restricted Stock Unit Award, the Board
        will determine the consideration, if any, to be paid by the Holder upon delivery of each share of Common Stock subject to the Restricted Stock Unit Award. The consideration to be paid (if any) by the Holder for each share of Common Stock subject to
        a Restricted Stock Unit Award may be paid in any form of legal consideration that may be acceptable to the Board, in its sole discretion, and permissible under applicable law.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(b)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Vesting.</font>&#160; Each RSU Award under this Plan shall vest as follows:</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(i)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;Initial Grants: one-third of the shares subject to the RSU shall vest on each annual anniversary of the date of grant,
        provided that the Holder has, during the entire year prior to each vesting date, continuously served as a Non-Employee Director or as an Employee of or Consultant to the Company or any Affiliate.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 72pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">&#160;(ii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;Annual Grants: 100% of the shares subject to the RSU shall vest on (1) the annual anniversary of the date of grant, <font style="color: rgb(0, 0, 0);">or (2) the next regularly scheduled annual meeting of stockholders</font>, whichever occurs earlier, provided that the Holder has, during the entire period from the date of grant through such vesting date,
        continuously served as a Non-Employee Director or as an Employee of or Consultant to the Company or any Affiliate; provided such RSU Awards, once vested, will be settled on the July 15<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">th</sup> following the vesting date.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(c)</font>&#160;&#160;&#160;&#160;&#160;&#160; &#160;&#160; <font style="font-weight: bold;">Payment.</font>&#160; A Restricted Stock Unit Award may be settled by the delivery of shares
        of Common Stock, their cash equivalent, any combination thereof or in any other form of consideration, as determined by the Board and contained in the Restricted Stock Unit Award Agreement.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(d)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Additional Restrictions.</font>&#160; At the time of the grant of a Restricted Stock Unit
        Award, the Board, as it deems appropriate, may impose such restrictions or conditions that delay the delivery of the shares of Common Stock (or their cash equivalent) subject to a Restricted Stock Unit Award to a time after the vesting of such
        Restricted Stock Unit Award.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(e)</font>&#160;&#160;&#160;&#160;&#160;&#160; &#160; &#160; <font style="font-weight: bold;">Dividend Equivalents.</font>&#160; Dividend equivalents may be credited in respect of shares
        of Common Stock covered by a Restricted Stock Unit Award, as determined by the Board and contained in the Restricted Stock Unit Award Agreement.&#160; At the sole discretion of the Board, such dividend equivalents may be converted into additional shares
        of Common Stock covered by the Restricted Stock Unit Award in such manner as determined by the Board.&#160; Any additional shares covered by the Restricted Stock Unit Award credited by reason of such dividend equivalents will be subject to all of the
        same terms and conditions of the underlying Restricted Stock Unit Award Agreement 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);">(f)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Termination of Holder&#8217;s Continuous Service.</font>&#160; Except as otherwise provided in the
        applicable Restricted Stock Unit Award Agreement, such portion of the Restricted Stock Unit Award that has not vested will be forfeited upon the Holder&#8217;s termination of Continuous Service.</div>
      <div>&#160;</div>
      <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div class="BRPFPageNumberArea" style="text-align: center;"><font style="font-size: 8pt; font-weight: normal; font-style: normal;">10</font></div>
        <div class="BRPFPageBreak" 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>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z0d8af2627b2f425ca5846684abbe509d" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

            <tr style="vertical-align: top;">
              <td style="vertical-align: top; width: 36pt;">
                <div style="text-align: justify;"><font style="font-weight: bold; color: rgb(0, 0, 0);">9.</font></div>
              </td>
              <td style="align: left; vertical-align: top; width: auto;">
                <div style="text-align: justify;"><font style="font-weight: bold; font-variant: small-caps;">Covenants of the Company.</font></div>
              </td>
            </tr>

        </table>
      </div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Availability of Shares.</font>&#160; During the terms of the Stock Awards, the Company shall
        keep available at all times the number of shares of Common Stock required to satisfy such Stock Awards.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><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;">Securities Law Compliance.</font>&#160; The Company shall seek to obtain from each regulatory
        commission or agency having jurisdiction over the Plan such authority as may be required to grant Stock Awards and to issue and sell shares of Common Stock upon exercise of the Stock Awards; provided, however, that this undertaking shall not
        require the Company to register under the Securities Act the Plan, any Stock Award or any Common Stock issued or issuable pursuant to any such Stock Award.&#160; If, after reasonable efforts, the Company is unable to obtain from any such regulatory
        commission or agency the authority which counsel for the Company deems necessary for the lawful issuance and sale of Common Stock under the Plan, the Company shall be relieved from any liability for failure to issue and sell Common Stock upon
        exercise of such Stock Awards unless and until such authority is obtained.&#160; A Non-Employee Director shall not be eligible for the grant of a Stock Award or the subsequent issuance of Common Stock pursuant to the Stock Award if such grant or
        issuance would violate any applicable securities law.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><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-weight: bold;">No Obligation to Notify or Minimize Taxes.&#160; </font>The Company shall have no duty or
        obligation to any Holder to advise such Holder (or the estate of, or transferee of, such Holder) as to the time or manner of exercising such Stock Award.&#160; Furthermore, the Company shall have no duty or obligation to warn or otherwise advise such
        Holder (or the estate of, or transferee of, such Holder) of a pending termination or expiration of a Stock Award or a possible period in which the Stock Award may not be exercised.&#160; The Company has no duty or obligation to minimize the tax
        consequences of a Stock Award to the Holder of such Stock Award.</div>
      <div>&#160;</div>
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z281a971f1a6c499f8b8d81df19424530" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

            <tr style="vertical-align: top;">
              <td style="vertical-align: top; width: 36pt;">
                <div style="text-align: justify;"><font style="font-weight: bold; color: rgb(0, 0, 0);">10.</font></div>
              </td>
              <td style="align: left; vertical-align: top; width: auto;">
                <div style="text-align: justify;"><font style="font-weight: bold; font-variant: small-caps;">Use of Proceeds from Stock.</font></div>
              </td>
            </tr>

        </table>
      </div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;">Proceeds from the sale of Common Stock pursuant to Options or RSU Awards (if any) shall constitute general funds of the Company.</div>
      <div>&#160;</div>
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z8cc6a5c223b348dda23544a22e66cb92" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

            <tr style="vertical-align: top;">
              <td style="vertical-align: top; width: 36pt;">
                <div style="text-align: justify;"><font style="font-weight: bold; color: rgb(0, 0, 0);">11.</font></div>
              </td>
              <td style="align: left; vertical-align: top; width: auto;">
                <div style="text-align: justify;"><font style="font-weight: bold; font-variant: small-caps;">Miscellaneous.</font></div>
              </td>
            </tr>

        </table>
      </div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Acceleration of Exercisability and Vesting.</font>&#160; The Board shall have the power to
        accelerate the time at which a Stock Award may first be exercised or the time during which a Stock Award or any part thereof will vest in accordance with the Plan, notwithstanding the provisions in the Stock Award stating the time at which it may
        first be exercised or the time during which it will vest.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><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;">Stockholder Rights.</font>&#160; No Holder shall be deemed to be the holder of, or to have any
        of the rights of a holder with respect to, any shares of Common Stock subject to such Stock Award unless and until such Holder has satisfied all requirements for exercise of the Option or settlement of the RSU Award, as applicable, pursuant to its
        terms.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><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-weight: bold;">No Service Rights.</font>&#160; Nothing in the Plan or any instrument executed or Stock Award
        granted pursuant thereto shall confer upon any Holder any right to continue to serve the Company as a Non-Employee Director or shall affect the right of the Company or an Affiliate to terminate (i) the employment of an Employee with or without
        notice and with or without cause, (ii) the service of a Consultant pursuant to the terms of such Consultant&#8217;s agreement with the Company or an Affiliate or (iii) the service of a Director pursuant to the Bylaws of the Company or an Affiliate, and
        any applicable provisions of the corporate law of the state in which the Company or the Affiliate is incorporated, as the case may be.</div>
      <div>&#160;</div>
      <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div class="BRPFPageNumberArea" style="text-align: center;"><font style="font-size: 8pt; font-weight: normal; font-style: normal;">11</font></div>
        <div class="BRPFPageBreak" 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; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(d)</font>&#160;&#160;&#160;&#160;&#160; &#160; <font style="font-weight: bold;">Investment Assurances.</font>&#160; The Company may require a Holder, as a condition of
        exercising or acquiring Common Stock under any Award, (i) to give written assurances satisfactory to the Company as to the Holder&#8217;s knowledge and experience in financial and business matters and/or to employ a purchaser representative reasonably
        satisfactory to the Company who is knowledgeable and experienced in financial and business matters and that he or she is capable of evaluating, alone or together with the purchaser representative, the merits and risks of exercising the Stock Award;
        and (ii) to give written assurances satisfactory to the Company stating that the Holder is acquiring the Common Stock subject to the Stock Award for the Holder&#8217;s own account and not with any present intention of selling or otherwise distributing
        the Common Stock.&#160; The foregoing requirements, and any assurances given pursuant to such requirements, shall be inoperative if (1) the issuance of the shares of Common Stock upon the exercise or acquisition of Common Stock under the Stock Award has
        been registered under a then currently effective registration statement under the Securities Act or (2) as to any particular requirement, a determination is made by counsel for the Company that such requirement need not be met in the circumstances
        under the then applicable securities laws.&#160; The Company may, upon advice of counsel to the Company, place legends on stock certificates issued under the Plan as such counsel deems necessary or appropriate in order to comply with applicable
        securities laws, including, but not limited to, legends restricting the transfer of the Common Stock.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(e)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Withholding Obligations.</font>&#160; To the extent provided by the terms of the applicable
        Option Agreement or RSU Award Agreement, the Holder may satisfy any federal, state or local tax withholding obligation relating to the exercise or acquisition of Common Stock under a Stock Award by any of the following means (in addition to the
        Company&#8217;s right to withhold from any compensation paid to the Holder by the Company) or by a combination of such means:&#160; (i) tendering a cash payment; (ii) authorizing the Company to withhold shares of Common Stock from the shares of Common Stock
        otherwise issuable to the Holder as a result of the exercise or acquisition of Common Stock under the Stock Award, <font style="font-style: italic;">provided, however</font>, that no shares of Common Stock are withheld with a value exceeding the
        minimum amount of tax required to be withheld by law (or such lower amount as may be necessary to avoid variable award accounting); or (iii) delivering to the Company owned and unencumbered shares of Common Stock.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(f)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Electronic Delivery</font>.&#160; Any reference herein to a &#8220;written&#8221; agreement or document
        shall include any agreement or document delivered electronically or posted on the Company&#8217;s intranet (or other shared electronic medium controlled by the Company to which the Holder has access).</div>
      <div>&#160;</div>
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zb7f71e3fc49f41b08b952360afd9c8d7" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

            <tr style="vertical-align: top;">
              <td style="vertical-align: top; width: 36pt;">
                <div style="text-align: justify;"><font style="font-weight: bold; color: rgb(0, 0, 0);">12.</font></div>
              </td>
              <td style="align: left; vertical-align: top; width: auto;">
                <div style="text-align: justify;"><font style="font-weight: bold; font-variant: small-caps;">Adjustments upon Changes in Stock.</font></div>
              </td>
            </tr>

        </table>
      </div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Capitalization Adjustments.</font>&#160; If any change is made in, or other event occurs with
        respect to, the Common Stock subject to the Plan, or subject to any Stock Award, without the receipt of consideration by the Company (through merger, consolidation, reorganization, recapitalization, reincorporation, stock dividend, dividend in
        property other than cash, stock split, liquidating dividend, combination of shares, exchange of shares, change in corporate structure or other transaction not involving the receipt of consideration by the Company) (each, a &#8220;Capitalization
        Adjustment&#8221;), the Plan will be appropriately adjusted in the class(es) and maximum number of securities subject both to the Plan pursuant to subsection 4(a) and to the nondiscretionary Stock Awards specified in Section 6, and the outstanding Stock
        Awards will be appropriately adjusted in the class(es) and number of securities and price per share of Common Stock subject to such outstanding Stock Awards.&#160; The Board shall make such adjustments, and its determination shall be final, binding and
        conclusive.&#160; (The conversion of any convertible securities of the Company shall not be treated as a transaction &#8220;without receipt of consideration&#8221; by the Company.)</div>
      <div>&#160;</div>
      <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div class="BRPFPageNumberArea" style="text-align: center;"><font style="font-size: 8pt; font-weight: normal; font-style: normal;">12</font></div>
        <div class="BRPFPageBreak" 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; text-indent: 36pt;"><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;">Dissolution or Liquidation.</font>&#160; In the event of a dissolution or liquidation of the
        Company, then all outstanding Stock Awards shall terminate immediately prior to the completion of such dissolution or liquidation.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(c)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Corporate Transaction.</font>&#160; In the event of a Corporate Transaction, any surviving
        corporation or acquiring corporation may assume any or all Stock Awards outstanding under the Plan or may substitute similar stock awards for Stock Awards outstanding under the Plan (it being understood that similar stock awards include, but are
        not limited to, options to acquire, or restricted stock unit rights to receive, the same consideration paid to the stockholders or the Company, as the case may be, pursuant to the Corporate Transaction).&#160; In the event that any surviving corporation
        or acquiring corporation does not assume any or all such outstanding Stock Awards or substitute similar stock awards for such outstanding Stock Awards, then with respect to Stock Awards that have been neither assumed nor substituted and that are
        held by Holders whose Continuous Service has not terminated prior to the effective time of the Corporate Transaction, the vesting of such Stock Awards (and, if applicable, the time at which such Stock Awards may be exercised) shall (contingent upon
        the effectiveness of the Corporate Transaction) be accelerated in full to a date prior to the effective time of such Corporate Transaction as the Board shall determine (or, if the Board shall not determine such a date, to the date that is 5 days
        prior to the effective time of the Corporate Transaction), and the Stock Awards shall terminate if not exercised at or prior to such effective time.&#160; With respect to Stock Awards outstanding under the Plan that have been neither assumed nor
        substituted and that are held by Holders whose Continuous Service has terminated prior to the effective time of the Corporate Transaction, the vesting of such Stock Awards (and, if applicable, the time at which such Stock Award may be exercised)
        shall not be accelerated unless otherwise provided in a written agreement between the Company or any Affiliate and the holder of such Stock Award, and such Stock Awards shall terminate if not exercised prior to the effective time of the Corporate
        Transaction.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(d)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Change in Control.</font>&#160; Notwithstanding any other provisions of the Plan to the
        contrary, if a Change in Control occurs and the Holder&#8217;s Continuous Service has not terminated prior to the effective date of such Change in Control, then the vesting and exercisability of the shares of Common Stock subject to the Holder&#8217;s Stock
        Awards shall be accelerated in full as of the effective date of the Change in Control.&#160; Following such Change in Control (other than a Change in Control resulting from a plan of complete dissolution or liquidation of the Company) and
        notwithstanding any other provision of the Plan to the contrary and provided that the Holder&#8217;s Continuous Service has not terminated prior to the effective date of the Change in Control, then the Holder&#8217;s Options shall expire on the earliest of (i)
        12 months following the effective date of such Change in Control or (ii) the Expiration Date indicated in the Holder&#8217;s Grant Notice.</div>
      <div>&#160;</div>
      <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div class="BRPFPageNumberArea" style="text-align: center;"><font style="font-size: 8pt; font-weight: normal; font-style: normal;">13</font></div>
        <div class="BRPFPageBreak" 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; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(e)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-weight: bold;">Parachute Payments.</font>&#160; If any payment or benefit the Holder would receive pursuant to
        a Change in Control from the Company or otherwise (&#8220;Payment&#8221;) would (i) constitute a &#8220;parachute payment&#8221; within the meaning of Section 280G of the Code, and (ii) but for this sentence, be subject to the excise tax imposed by Section 4999 of the
        Code (the &#8220;Excise Tax&#8221;), then such Payment shall be reduced to the Reduced Amount.&#160; The &#8220;Reduced Amount&#8221; shall be either (x) the largest portion of the Payment that would result in no portion of the Payment being subject to the Excise Tax or (y)
        the largest portion, up to and including the total, of the Payment, whichever amount, after taking into account all applicable federal, state and local employment taxes, income taxes, and the Excise Tax (all computed at the highest applicable
        marginal rate), results in the Holder&#8217;s receipt, on an after-tax basis, of the greater amount of the Payment notwithstanding that all or some portion of the Payment may be subject to the Excise Tax.&#160; If a reduction in a Payment is required pursuant
        to the preceding sentence and the Reduced Amount is determined pursuant to clause (x) of the preceding sentence, the reduction shall occur in the manner (the &#8220;<font style="font-weight: bold; font-style: italic;">Reduction Method</font>&#8221;) that
        results in the greatest economic benefit for Holder.&#160; If more than one method of reduction will result in the same economic benefit, the items so reduced will be reduced pro rata (the &#8220;<font style="font-weight: bold; font-style: italic;">Pro Rata
          Reduction Method</font>&#8221;).&#160; Notwithstanding the foregoing, if the Reduction Method or the Pro Rata Reduction Method would result in any portion of the Payment being subject to taxes pursuant to Section 409A of the Code that would not otherwise be
        subject to taxes pursuant to Section 409A of the Code, then the Reduction Method and/or the Pro Rata Reduction Method, as the case may be, shall be modified so as to avoid the imposition of taxes pursuant to Section 409A of the Code as follows:&#160;
        (A) as a first priority, the modification shall preserve to the greatest extent possible, the greatest&#160; economic benefit for Holder as determined on an after-tax basis; (B) as a second priority, Payments that are contingent on future events (e.g.,
        being terminated without cause), shall be reduced (or eliminated) before Payments that are not contingent on future events; and (C) as a third priority, Payments that are &#8220;deferred compensation&#8221; within the meaning of Section 409A of the Code shall
        be reduced (or eliminated) before Payments that are not deferred compensation within the meaning of Section 409A of the Code.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;">The accounting firm engaged by the Company for general audit purposes as of the day prior to the effective date of the Change in Control shall perform the foregoing calculations.&#160; If the accounting
        firm so engaged by the Company is serving as accountant or auditor for the individual, entity or group effecting the Change in Control, the Company shall appoint a nationally recognized accounting firm to make the determinations required
        hereunder.&#160; The Company shall bear all expenses with respect to the determinations by such accounting firm required to be made hereunder.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt; color: rgb(0, 0, 0);">The accounting firm engaged to make the determinations hereunder shall provide its calculations, together with detailed supporting documentation, to the Holder and the Company
        within 15 calendar days after the date on which the Holder&#8217;s right to a Payment is triggered (if requested at that time by the Holder or the Company) or such other time as requested by the Holder or the Company.&#160; If the accounting firm determines
        that no Excise Tax is payable with respect to a Payment, either before or after the application of the Reduced Amount, it shall furnish the Company and the Holder with an opinion reasonably acceptable to the Holder that no Excise Tax will be
        imposed with respect to such Payment.&#160; Any good faith determinations of the accounting firm made hereunder shall be final, binding and conclusive upon the Holder and the Company.</div>
      <div>&#160;</div>
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z7b01eea53f794cbb8bb9c0b3e9289b6b" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

            <tr style="vertical-align: top;">
              <td style="vertical-align: top; width: 36pt;">
                <div style="text-align: justify;"><font style="font-weight: bold; color: rgb(0, 0, 0);">13.</font></div>
              </td>
              <td style="align: left; vertical-align: top; width: auto;">
                <div style="text-align: justify;"><font style="font-weight: bold; font-variant: small-caps;">Amendment of the Plan and Stock Awards.</font></div>
              </td>
            </tr>

        </table>
      </div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Amendment of Plan.</font>&#160; The Board at any time, and from time to time, may amend the
        Plan.&#160; However, except as provided in Section 12(a) relating to Capitalization Adjustments, no amendment shall be effective unless approved by the stockholders of the Company to the extent stockholder approval is necessary to satisfy the
        requirements of Rule 16b-3 or any Nasdaq or securities exchange listing requirements.</div>
      <div>&#160;</div>
      <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div class="BRPFPageNumberArea" style="text-align: center;"><font style="font-size: 8pt; font-weight: normal; font-style: normal;">14</font></div>
        <div class="BRPFPageBreak" 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; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(b)</font>&#160;&#160;&#160;&#160;&#160;&#160; &#160;&#160; <font style="font-weight: bold;">Stockholder Approval.</font>&#160; The Board, in its sole discretion, may submit any other
        amendment to the Plan for stockholder approval.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(c)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">No Impairment of Rights.</font>&#160; Rights under any Stock Award granted before amendment of
        the Plan shall not be impaired by any amendment of the Plan unless (i) the Company requests the consent of the Holder and (ii) the Holder consents in writing.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(d)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold;">Amendment of Stock Awards.</font>&#160; The Board at any time, and from time to time, may amend
        the terms of any one or more Stock Awards; <font style="font-style: italic;">provided, however</font>, that the rights under any Stock Award shall not be impaired by any such amendment unless (i) the Company requests the consent of the Holder and
        (ii) the Holder consents in writing.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(e)</font>&#160;&#160;&#160;&#160; &#160; &#160;&#160; <font style="font-weight: bold;">Prohibition on Reduction of Exercise Prices, Cancellation and Re-Grant of Stock Awards.</font>&#160;
        Neither the Board nor any Committee (or subcommittee) shall have the authority to: (i) reduce the exercise price of any outstanding Options under the Plan, or (ii) cancel any outstanding Options 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 under the Plan, unless the stockholders of the Company have approved such an action within 12 months prior to such an event.&#160; Notwithstanding the
        foregoing, this paragraph will not be construed to apply to &#8220;issuing or assuming a stock option in a transaction to which section 424(a) applies,&#8221; within the meaning of Section 424 of the Code.&#8221;</div>
      <div>&#160;</div>
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zf9fc190f3bb2441b86239374daed3c65" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

            <tr style="vertical-align: top;">
              <td style="vertical-align: top; width: 36pt;">
                <div style="text-align: justify;"><font style="font-weight: bold; color: rgb(0, 0, 0);">14.</font></div>
              </td>
              <td style="align: left; vertical-align: top; width: auto;">
                <div style="text-align: justify;"><font style="font-weight: bold; font-variant: small-caps;">Termination or Suspension of the Plan.</font></div>
              </td>
            </tr>

        </table>
      </div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(a)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#160; <font style="font-weight: bold;">Plan Term</font>.&#160; The Board may suspend or terminate the Plan at any time.&#160; Unless
        sooner terminated, the Plan shall terminate on June 1, 2030.&#160; No Stock Awards may be granted under the Plan while the Plan is suspended or after it is terminated.</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">(b)</font>&#160;&#160;&#160;&#160;&#160; &#160;&#160; <font style="font-weight: bold;">No Impairment of Rights.</font>&#160; Suspension or termination of the Plan shall not impair
        rights and obligations under any Stock Award granted while the Plan is in effect except with the written consent of the Holder.</div>
      <div>&#160;</div>
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z5746bb147ece4e01a5147730d09c43d1" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

            <tr style="vertical-align: top;">
              <td style="vertical-align: top; width: 36pt;">
                <div style="text-align: justify;"><font style="font-weight: bold; color: rgb(0, 0, 0);">15.</font></div>
              </td>
              <td style="align: left; vertical-align: top; width: auto;">
                <div style="text-align: justify;"><font style="font-weight: bold; font-variant: small-caps;">Effective Date of Plan.</font></div>
              </td>
            </tr>

        </table>
      </div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;">The Plan shall become effective as determined by the Board, but no Stock Award shall be exercised unless and until the Plan has been approved by the stockholders of the Company, which approval
        shall be within 12 months before or after the date the Plan is adopted by the Board.</div>
      <div>&#160;</div>
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zcfbf03a4431244ce8fd07cce73c92e41" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

            <tr style="vertical-align: top;">
              <td style="vertical-align: top; width: 36pt;">
                <div style="text-align: justify;"><font style="font-weight: bold; color: rgb(0, 0, 0);">16.</font></div>
              </td>
              <td style="align: left; vertical-align: top; width: auto;">
                <div style="text-align: justify;"><font style="font-weight: bold; font-variant: small-caps;">Choice of Law.</font></div>
              </td>
            </tr>

        </table>
      </div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;">The law of the State of California shall govern all questions concerning the construction, validity and interpretation of this Plan without regard to such state&#8217;s conflict of laws rules.</div>
      <div style="text-align: justify;"> <br>
      </div>
      <div style="text-align: justify;"> <br>
      </div>
      <div style="text-align: center;"> <font style="font-size: 8pt; font-weight: normal; font-style: normal;">15</font></div>
      <div style="text-align: justify; text-indent: 36pt;">
        <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>
    </div>
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</DOCUMENT>
<DOCUMENT>
<TYPE>EX-10.3
<SEQUENCE>4
<FILENAME>ex10-3.htm
<DESCRIPTION>EXHIBIT 10.3
<TEXT>
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      <div style="text-align: right; font-weight: bold;">Exhibit 10.3</div>
      <div>&#160;</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;">Restricted Stock Unit Grant Notice</font></div>
      <div style="text-align: center; font-weight: bold;">(<font style="font-variant: small-caps;">Amended &amp; Restated 2002 Non-Employee Directors&#8217; Stock Option Plan)</font></div>
      <div>&#160;</div>
      <div style="text-align: justify;">Ionis Pharmaceuticals, Inc. (the <font style="font-weight: bold; font-style: italic;">&#8220;Company&#8221;</font>), pursuant to its Amended &amp; Restated 2002 Non-Employee Directors&#8217; Stock Option Plan (the <font style="font-weight: bold; font-style: italic;">&#8220;Plan&#8221;</font>), hereby awards to Participant a Restricted Stock Unit 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 Restricted Stock Unit Agreement, 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 Restricted Stock Unit 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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          <tr>
            <td style="width: 50%; vertical-align: top; padding-bottom: 2px;">
              <div style="text-align: justify;">Participant:</div>
            </td>
            <td style="width: 45%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);"><br>
            </td>
            <td style="width: 5%; vertical-align: top; padding-bottom: 2px;" colspan="1">&#160;</td>
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          <tr>
            <td style="width: 50%; vertical-align: top; padding-bottom: 2px;">
              <div style="text-align: justify;">Date of Grant:</div>
            </td>
            <td style="width: 45%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);"><br>
            </td>
            <td style="width: 5%; vertical-align: top; padding-bottom: 2px;" colspan="1">&#160;</td>
          </tr>
          <tr>
            <td style="width: 50%; vertical-align: top; padding-bottom: 2px;">
              <div style="text-align: justify;">Delivery Date:</div>
            </td>
            <td style="width: 45%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);"><br>
            </td>
            <td style="width: 5%; vertical-align: top; padding-bottom: 2px;" colspan="1">&#160;</td>
          </tr>
          <tr>
            <td style="width: 50%; vertical-align: top; padding-bottom: 2px;">
              <div style="text-align: justify;">Number of Stock Units Subject to Award:</div>
            </td>
            <td style="width: 45%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);"><br>
            </td>
            <td style="width: 5%; vertical-align: top; padding-bottom: 2px;" colspan="1">&#160;</td>
          </tr>
          <tr>
            <td style="width: 50%; vertical-align: top; padding-bottom: 2px;">
              <div style="text-align: justify;">Consideration:</div>
            </td>
            <td style="width: 45%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
              <div style="text-align: justify;">Participant&#8217;s Services</div>
            </td>
            <td style="width: 5%; vertical-align: top; padding-bottom: 2px;" colspan="1">&#160;</td>
          </tr>

      </table>
      <div><br>
      </div>
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          <tr>
            <td style="width: 107.1pt; vertical-align: top;"><font style="font-weight: bold;">Vesting Schedule</font>:</td>
            <td style="width: auto; vertical-align: top; text-align: justify;">
              <div>100% of the Stock Units subject to this Award will vest either on (1) the annual anniversary of the Date of Grant, or (2) the next regularly scheduled annual meeting of stockholders of the Company, whichever occurs earlier.&#160;
                Notwithstanding the foregoing, vesting shall terminate upon the Participant&#8217;s termination of Continuous Service.</div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
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          <tr>
            <td style="width: 108pt; 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 the issuance schedule set forth in Section 6 of the Restricted Stock Unit Agreement.</div>
            </td>
          </tr>

      </table>
      <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 Restricted Stock Unit Grant Notice, the Restricted
        Stock Unit Agreement and the Plan.&#160; Participant further acknowledges that as of the Date of Grant, this Restricted Stock Unit Grant Notice, the Restricted Stock Unit Agreement and the Plan set forth the entire understanding between Participant and
        the Company regarding the Award and supersedes all prior oral and written agreements on that subject.</div>
      <div>&#160;</div>
      <div>
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            <tr>
              <td style="width: 3%; vertical-align: top;" rowspan="1" colspan="2">
                <div style="text-align: justify; font-variant: small-caps; font-weight: bold;">Ionis Pharmaceuticals, Inc.</div>
              </td>
              <td style="width: 4%; vertical-align: top;">&#160;</td>
              <td style="width: 48%; vertical-align: top;">
                <div style="text-align: justify; font-variant: small-caps; font-weight: bold;">Participant:</div>
              </td>
            </tr>
            <tr>
              <td style="width: 3%; vertical-align: top;" rowspan="1">&#160;</td>
              <td style="width: 45%; vertical-align: top;" rowspan="1">&#160;</td>
              <td style="width: 4%; vertical-align: top;" rowspan="1">&#160;</td>
              <td style="width: 48%; vertical-align: top;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="width: 3%; vertical-align: top; padding-bottom: 2px;">
                <div style="text-align: justify;">By:</div>
              </td>
              <td style="width: 45%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
              <td style="width: 4%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
              <td style="width: 48%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
            </tr>
            <tr>
              <td style="width: 3%; vertical-align: top;">&#160;</td>
              <td style="width: 45%; vertical-align: top;">
                <div style="text-align: center;">Signature</div>
              </td>
              <td style="width: 4%; vertical-align: top;">&#160;</td>
              <td style="width: 48%; vertical-align: top;">
                <div style="text-align: center;">Signature</div>
              </td>
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        <div> <br>
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                <div style="text-align: justify;">Title:</div>
              </td>
              <td style="width: 43%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
              <td style="width: 4%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
              <td style="width: 5%; vertical-align: top; padding-bottom: 2px;">
                <div style="text-align: justify;">Date:</div>
              </td>
              <td style="width: 43%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top;" rowspan="1">&#160;</td>
              <td style="width: 43%; vertical-align: top;" rowspan="1">&#160;</td>
              <td style="width: 4%; vertical-align: top;" rowspan="1">&#160;</td>
              <td style="vertical-align: top;" colspan="2" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; padding-bottom: 2px;">
                <div style="text-align: justify;">Date:</div>
              </td>
              <td style="width: 43%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
              <td style="width: 4%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
              <td style="vertical-align: top; padding-bottom: 2px;" colspan="2">&#160;</td>
            </tr>

        </table>
      </div>
      <div>&#160;</div>
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          <tr>
            <td style="width: 81pt; vertical-align: top;"><font style="font-weight: bold; font-variant: small-caps;">Attachments</font>:</td>
            <td style="width: auto; vertical-align: top;">
              <div>Restricted Stock Unit Agreement, Amended &amp; Restated 2002 Non-Employee Directors&#8217; Stock Option Plan</div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
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      <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;">Restricted Stock Unit Grant Notice</div>
      <div style="text-align: center; font-variant: small-caps; font-weight: bold;">For Deferred Restricted Stock Units</div>
      <div style="text-align: center; font-weight: bold;">(<font style="font-variant: small-caps;">Amended &amp; Restated 2002 Non-Employee Directors&#8217; Stock Option Plan)</font></div>
      <div>&#160;</div>
      <div style="text-align: justify;">Ionis Pharmaceuticals, Inc. (the <font style="font-weight: bold; font-style: italic;">&#8220;Company&#8221;</font>), pursuant to its Amended &amp; Restated 2002 Non-Employee Directors&#8217; Stock Option Plan (the <font style="font-weight: bold; font-style: italic;">&#8220;Plan&#8221;</font>), hereby awards to Participant a Restricted Stock Unit 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 Restricted Stock Unit Agreement (the &#8220;<font style="font-weight: bold; font-style: italic;">RSU</font>&#160;<font style="font-weight: bold; font-style: italic;">Agreement</font>&#8221;), 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 RSU 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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          <tr>
            <td style="width: 50%; vertical-align: top; padding-bottom: 2px;">
              <div>Participant:</div>
            </td>
            <td style="width: 45.46%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
              <div>&#171;Name&#187;</div>
            </td>
            <td style="width: 5%; vertical-align: top; padding-bottom: 2px;" colspan="1">&#160;</td>
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          <tr>
            <td style="width: 50%; vertical-align: top; padding-bottom: 2px;">
              <div>Date of Grant:</div>
            </td>
            <td style="width: 45.46%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
              <div>&#171;Date&#187;</div>
            </td>
            <td style="width: 5%; vertical-align: top; padding-bottom: 2px;" colspan="1">&#160;</td>
          </tr>
          <tr>
            <td style="width: 50%; vertical-align: top; padding-bottom: 2px;">
              <div>Vesting Commencement Date:</div>
            </td>
            <td style="width: 45.46%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
              <div>&#171;Date&#187;</div>
            </td>
            <td style="width: 5%; vertical-align: top; padding-bottom: 2px;" colspan="1">&#160;</td>
          </tr>
          <tr>
            <td style="width: 50%; vertical-align: top; padding-bottom: 2px;">
              <div>Number of Stock Units Subject to Award:</div>
            </td>
            <td style="width: 45.46%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
              <div>&#171;Shares&#187;</div>
            </td>
            <td style="width: 5%; vertical-align: top; padding-bottom: 2px;" colspan="1">&#160;</td>
          </tr>
          <tr>
            <td style="width: 50%; vertical-align: top; padding-bottom: 2px;">
              <div>Consideration:</div>
            </td>
            <td style="width: 45.46%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
              <div>Participant&#8217;s Services</div>
            </td>
            <td style="width: 5%; vertical-align: top; padding-bottom: 2px;" colspan="1">&#160;</td>
          </tr>

      </table>
      <div><br>
      </div>
      <table cellspacing="0" cellpadding="0" id="z761e3ad9cd654501b134de4af0954a28" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

          <tr>
            <td style="width: 108pt; vertical-align: top;"><font style="font-weight: bold;">Vesting Schedule</font>:</td>
            <td style="width: auto; vertical-align: top; text-align: justify;">
              <div>100% of the Stock Units subject to this Award will vest either on (1) the annual anniversary of the Date of Grant, or (2) the next regularly scheduled annual meeting of stockholders of the Company, whichever occurs earlier.&#160;
                Notwithstanding the foregoing, vesting shall terminate upon the Participant&#8217;s termination of Continuous Service.</div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <table cellspacing="0" cellpadding="0" id="z6cfd55cf58544de284b49b63d6ac7d33" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

          <tr>
            <td style="width: 108pt; vertical-align: top; font-weight: bold;">Issuance Schedule:</td>
            <td style="width: auto; vertical-align: top; text-align: justify;">
              <div>Subject to Sections 6 and 19 of the RSU Agreement, and subject to any Capitalization Adjustment, one share of Common Stock (or its cash equivalent, at the discretion of the Company) will be issued for each Stock Unit that has vested
                under this Award on the first to occur of the following as indicated by the check mark below (such date, the &#8220;<font style="font-weight: bold; font-style: italic;">Settlement Date</font>&#8221;):</div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 0pt; margin-left: 108pt;">&#9744; <font style="font-weight: bold;"><u>DEFERRAL CHOICE A</u></font>:</div>
      <div><br>
      </div>
      <table cellspacing="0" cellpadding="0" id="zd80f19088dc54b79a204cda4861fbec7" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

          <tr>
            <td style="width: 108pt;"><br>
            </td>
            <td style="width: 18pt; vertical-align: top;">&#8226;</td>
            <td style="width: auto; vertical-align: top; text-align: justify;">
              <div>The fifth anniversary of the vesting date;</div>
            </td>
          </tr>

      </table>
      <div>&#160;</div>
      <table cellspacing="0" cellpadding="0" id="z9cb1983c7db54276bd199099717b523b" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

          <tr>
            <td style="width: 108pt;"><br>
            </td>
            <td style="width: 18pt; vertical-align: top;">&#8226;</td>
            <td style="width: auto; vertical-align: top; text-align: justify;">
              <div>The thirtieth (30<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">th</sup>) day following the Participant&#8217;s &#8220;separation from service&#8221; (as defined under Treasury Regulation Section 1.409A-1(h), without regard to
                any alternative definitions therein, a &#8220;<font style="font-weight: bold; font-style: italic;">Separation from Service</font>&#8221;); or</div>
            </td>
          </tr>

      </table>
      <div>&#160;</div>
      <table cellspacing="0" cellpadding="0" id="ze5b9a51411264652859bb0cac92b7253" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

          <tr>
            <td style="width: 108pt;"><br>
            </td>
            <td style="width: 18pt; vertical-align: top;">&#8226;</td>
            <td style="width: auto; vertical-align: top; text-align: justify;">
              <div>The date of a change in control of the Company that also would constitute a &#8220;change in control event&#8221; (as defined under Treasury Regulation Section 1.409A-3(i)(5), a &#8220;<font style="font-weight: bold; font-style: italic;">409A Change in
                  Control</font>&#8221;).</div>
            </td>
          </tr>

      </table>
      <div>&#160;</div>
      <div style="text-align: justify; margin-left: 108pt;">&#9744; <font style="font-weight: bold;"><u>DEFERRAL CHOICE B</u>:</font></div>
      <div>&#160;</div>
      <table cellspacing="0" cellpadding="0" id="z413310c5c32d4f5fb8c12977a519f898" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

          <tr>
            <td style="width: 108pt;"><br>
            </td>
            <td style="width: 18pt; vertical-align: top;">&#8226;</td>
            <td style="width: auto; vertical-align: top; text-align: justify;">
              <div>The thirtieth (30<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">th</sup>) day following the Participant&#8217;s Separation from Service; or</div>
            </td>
          </tr>

      </table>
      <div>&#160;</div>
      <table cellspacing="0" cellpadding="0" id="zb24bc14ea989421b803f3857a3ea53ac" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

          <tr>
            <td style="width: 108pt;"><br>
            </td>
            <td style="width: 18pt; vertical-align: top;">&#8226;</td>
            <td style="width: auto; vertical-align: top; text-align: justify;">
              <div>The date of a 409A Change in Control.</div>
            </td>
          </tr>

      </table>
      <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 Restricted Stock Unit Grant Notice, the RSU
        Agreement, and the Plan.&#160; Participant further acknowledges that as of the Date of Grant, this Restricted Stock Unit Grant Notice, the RSU Agreement, and the Plan set forth the entire understanding between Participant and the Company regarding the
        Award and supersedes all prior oral and written agreements on that subject.</div>
      <div style="text-align: justify;"> <br>
      </div>
      <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div class="BRPFPageBreak" style="page-break-after: always;">
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      </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;">

            <tr>
              <td style="width: 3%; vertical-align: top;" rowspan="1" colspan="2">
                <div style="text-align: justify; font-variant: small-caps; font-weight: bold;">Ionis Pharmaceuticals, Inc.</div>
              </td>
              <td style="width: 4%; vertical-align: top;">&#160;</td>
              <td style="width: 48%; vertical-align: top;">
                <div style="text-align: justify; font-variant: small-caps; font-weight: bold;">Participant:</div>
              </td>
            </tr>
            <tr>
              <td style="width: 3%; vertical-align: top;" rowspan="1">&#160;</td>
              <td style="width: 45%; vertical-align: top;" rowspan="1">&#160;</td>
              <td style="width: 4%; vertical-align: top;" rowspan="1">&#160;</td>
              <td style="width: 48%; vertical-align: top;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="width: 3%; vertical-align: top; padding-bottom: 2px;">
                <div style="text-align: justify;">By:</div>
              </td>
              <td style="width: 45%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
              <td style="width: 4%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
              <td style="width: 48%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
            </tr>
            <tr>
              <td style="width: 3%; vertical-align: top;">&#160;</td>
              <td style="width: 45%; vertical-align: top;">
                <div style="text-align: center;">Signature</div>
              </td>
              <td style="width: 4%; vertical-align: top;">&#160;</td>
              <td style="width: 48%; vertical-align: top;">
                <div style="text-align: center;">Signature</div>
              </td>
            </tr>

        </table>
        <div> <br>
        </div>
      </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;">

            <tr>
              <td style="width: 5%; vertical-align: top; padding-bottom: 2px;">
                <div style="text-align: justify;">Title:</div>
              </td>
              <td style="width: 43%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
                <div style="text-align: justify;">EVP Finance &amp; CFO</div>
              </td>
              <td style="width: 4%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
              <td style="width: 5%; vertical-align: top; padding-bottom: 2px;">
                <div style="text-align: justify;">Date:</div>
              </td>
              <td style="width: 43%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top;" rowspan="1">&#160;</td>
              <td style="width: 43%; vertical-align: top;" rowspan="1">&#160;</td>
              <td style="width: 4%; vertical-align: top;" rowspan="1">&#160;</td>
              <td style="vertical-align: top;" colspan="2" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; padding-bottom: 2px;">
                <div style="text-align: justify;">Date:</div>
              </td>
              <td style="width: 43%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
              <td style="width: 4%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
              <td style="vertical-align: top; padding-bottom: 2px;" colspan="2">&#160;</td>
            </tr>

        </table>
      </div>
      <div><br>
      </div>
      <br>
      <table cellspacing="0" cellpadding="0" id="zbaae63c2543040169ff12a896fd4ac5f" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

          <tr>
            <td style="width: 81pt; vertical-align: top;"><font style="font-weight: bold; font-variant: small-caps;">Attachments</font>:</td>
            <td style="width: auto; vertical-align: top;">
              <div>Restricted Stock Unit Agreement, Amended &amp; Restated 2002 Non-Employee Directors&#8217; Stock Option Plan</div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div class="BRPFPageBreak" style="page-break-after: always;">
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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 2002 Non-Employee Directors&#8217;</div>
      <div style="text-align: center; font-variant: small-caps; font-weight: bold;">Stock Option Plan</div>
      <div style="text-align: center; font-variant: small-caps; font-weight: bold;"> <br>
      </div>
      <div style="text-align: center; font-variant: small-caps; font-weight: bold;">Restricted Stock Unit Agreement</div>
      <div>&#160;</div>
      <div style="text-align: justify; text-indent: 36pt;">Pursuant to the Restricted Stock Unit Grant Notice (&#8220;<font style="font-weight: bold; font-style: italic;">Grant Notice</font>&#8221;) and this Restricted Stock Unit Agreement 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 Restricted Stock Unit Award (the &#8220;<font style="font-weight: bold; font-style: italic;">Award</font>&#8221;) under its
        Amended &amp; Restated 2002 Non-Employee Director&#8217;s Stock Option 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 Restricted Stock Unit Agreement shall be deemed to be agreed to by the Company and you upon the earlier of (i) signing (or electronic acceptance) by you of the Restricted Stock Unit Grant Notice to which it is attached, and (ii) your
        receipt of shares of Common Stock under this Restricted Stock Unit Agreement.&#160; Capitalized terms not explicitly defined in this Restricted Stock Unit Agreement shall 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 Restricted Stock Unit Agreement and the Plan, the terms of the Plan shall 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; <font style="font-weight: bold; font-variant: small-caps;">Grant of the Award.&#160; &#160; </font>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 stock units indicated in the Grant Notice (the &#8220;<font style="font-weight: bold; font-style: italic;">Stock Units</font>&#8221;).&#160; As of the
        Date of Grant, the Company will credit to a bookkeeping account maintained by the Company for your benefit (the &#8220;<font style="font-weight: bold; font-style: italic;">Account</font>&#8221;) the number of Stock Units subject to the Award.&#160; 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 Stock Units 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: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">2.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold; font-variant: small-caps;">Vesting</font><font style="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;<font style="font-weight: bold;">In General.</font>&#160; Subject to the limitations contained herein, your Award will vest, if
        at all, in accordance with the vesting schedule provided in the Grant Notice, provided that vesting will cease upon the termination of your Continuous Service.&#160; Upon such termination of your Continuous Service, the Stock Units credited to the
        Account 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 Stock Units or the shares of Common Stock to be issued in respect of the Award.</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-weight: bold; font-variant: small-caps;">Number of Shares</font><font style="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; The number of Stock Units subject to your Award may be adjusted from time to time for Capitalization Adjustments, as
        provided in the Plan.</div>
      <div>&#160;</div>
      <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div class="BRPFPageBreak" 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; 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 Stock Units that become subject to the Award pursuant to this Section 3 and Section 7, if any, shall 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 Stock Units 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 3, no fractional shares or rights for fractional shares of Common Stock
        shall be created pursuant to this Section 3.&#160; The Board shall, 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 3.</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;">Securities Law Compliance</font><font style="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);">5.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="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 5.&#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="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; <font style="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, shall 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 shall 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; <font style="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; <font style="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 class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div class="BRPFPageBreak" 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; text-indent: 36pt;"><font style="font-weight: bold; color: rgb(0, 0, 0);">6.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#160; <font style="font-weight: bold; font-variant: small-caps;">Date of Issuance.&#160; </font>In the event that one or more Stock
        Units vests, subject to the satisfaction of the Withholding Obligation set forth in Section 10, the Company will issue to you one share of Common Stock for each vested Stock Unit on the Settlement Date determined under the Grant Notice, but in all
        cases, except as may be required by Section 19, not later than December 31 of the calendar year in which the Settlement Date occurs. If a scheduled delivery date falls on a date that is not a business day, such delivery date shall instead fall on
        the next following business day.</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; <font style="font-weight: bold; font-variant: small-caps;">Dividends.</font><font style="font-weight: bold;">&#160; </font>You
        shall be entitled to receive payments equal to any cash dividends and other distributions paid with respect to&#160; a corresponding number of shares to be issued in respect of the Stock Units covered by your Award, provided that if any such dividends
        or distributions are paid in shares, the Fair Market Value of such shares shall be converted into additional Stock Units covered by the Award, and further provided that such additional Stock Units shall be subject to the same forfeiture
        restrictions and restrictions on transferability as apply to the Stock Units 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);">8.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#160; <font style="font-weight: bold; font-variant: small-caps;">Restrictive Legends.</font>&#160; The shares issued in respect of
        your Award shall 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);">9.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#160; <font style="font-weight: bold; font-variant: small-caps;">Award not a Service Contract</font><font style="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; 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 Restricted Stock Unit Agreement (including, but not limited to, the vesting of your Award pursuant to the schedule set forth
        in Section 2 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 Restricted Stock Unit Agreement or the Plan shall:&#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 Restricted Stock Unit 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; By accepting this Award, you acknowledge and agree that the right to continue vesting in the Award pursuant to the schedule
        set forth in Section 2 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 Restricted Stock Unit 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 Restricted Stock Unit 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 shall 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 class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
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      </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;&#160; <font style="font-weight: bold; font-variant: small-caps;">Withholding Obligation.</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; On or before the time you receive a distribution of the 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-weight: bold; font-style: italic;">Withholding Obligation</font>&#8221;).&#160; Additionally, the Company may, in its sole
        discretion, satisfy all or any portion of the Withholding 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 to pursuant to Section 6) equal to the amount of such Withholding Obligation; provided, however, that the number of such shares of Common Stock so withheld shall 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;&#160; Unless the tax withholding obligations of the Company and/or any Affiliate are satisfied, the Company shall 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; 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;&#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 6) equal to the amount of such Withholding Obligation; provided, however, that the number of such shares of Common Stock so withheld shall
        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 class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div class="BRPFPageBreak" style="page-break-after: always;">
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      </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;&#160; <font style="font-weight: bold; font-variant: small-caps;">Unsecured Obligation.</font>&#160; Your Award is unfunded, and as a
        holder of a vested Award, you shall 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 shall 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 6 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, shall 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="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;&#160; <font style="font-weight: bold; font-variant: small-caps;">Other Documents</font><font style="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);">13.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold; font-variant: small-caps;">Notices</font><font style="font-weight: bold;">.</font>&#160; Any
        notices provided for in your Award or the Plan shall be given in writing and shall 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);">14.</font>&#160;&#160;&#160;&#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 shall be transferable to any one or more persons or entities, and
        all covenants and agreements hereunder shall 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; 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;&#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; This Agreement shall 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;&#160; All obligations of the Company under the Plan and this Agreement shall 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 class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
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      </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-weight: bold; font-variant: small-caps;">Governing Plan Document</font><font style="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 shall control.</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-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 shall 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 shall, 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);">17.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold; font-variant: small-caps;">Choice of Law</font><font style="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);">18.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="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 shall 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);">19.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-weight: bold; font-variant: small-caps;">Compliance with Section 409A of the Code</font>. This Award is
        intended to comply with U.S. Treasury Regulation Section 1.409A-3(a) and will be construed and administered in such a manner. Each installment of Stock Units that vests hereunder is intended to constitute a &#8220;separate payment&#8221; for purposes of
        Treasury Regulation Section 1.409A-2(b)(2). If you are a Specified Employee upon your Separation from Service, then the issuance of any shares, cash or other property that would otherwise be made on the date of your Separation from Service (or
        within the first six months thereafter as a result of your Separation from Service) will not be made on the originally scheduled date(s) and will instead be issued in a lump-sum on the earlier of (i) the date that is six months and one day after
        the date of the Separation from Service, (ii) the date of your death or (iii) a 409A Change in Control, but if and only if such delay in the issuance is necessary to avoid the imposition of taxation on you in respect of the shares, cash or property
        under Code Section 409A.</div>
      <div>&#160;</div>
      <div style="text-align: center;">*****</div>
      <div><br>
      </div>
      <div style="text-indent: 36pt;">This Restricted Stock Unit Agreement shall be deemed to be signed by the Company and the Participant upon the signing by the Participant of the Restricted Stock Unit Grant Notice to which it is attached.</div>
      <div><br>
      </div>
      <div>&#160;</div>
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<DOCUMENT>
<TYPE>EX-10.4
<SEQUENCE>5
<FILENAME>ex10-4.htm
<DESCRIPTION>EXHIBIT 10.4
<TEXT>
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      <div style="text-align: right;"><font style="font-weight: bold;">Exhibit 10.4</font><br>
      </div>
      <div style="text-align: right;"><font style="font-weight: bold;"> <br>
        </font></div>
      <div>
        <div style="text-align: right; font-variant: small-caps; font-weight: bold;">Execution Version</div>
      </div>
      <div><br>
      </div>
      <div>
        <div style="color: rgb(0, 0, 0); text-align: center;">Certain portions of this exhibit, marked by [***], have been excluded because they are both not material and are the type that the registrant treats as private or confidential</div>
        <div>&#160;</div>
        <div style="text-align: center; font-variant: small-caps; font-weight: bold;">HTT Research, Development, Option and License Agreement</div>
        <div style="font-weight: bold;">&#160;</div>
        <div style="text-align: center; font-variant: small-caps; font-weight: bold;">Among</div>
        <div style="text-align: center; font-variant: small-caps;"> <br>
        </div>
        <div style="text-align: center; font-variant: small-caps; font-weight: bold;">Isis Pharmaceuticals, Inc.,</div>
        <div>&#160;</div>
        <div style="text-align: center; font-variant: small-caps; font-weight: bold;">And</div>
        <div>&#160;</div>
        <div style="text-align: center; font-variant: small-caps; font-weight: bold;">F. Hoffmann-La Roche Ltd</div>
        <div>&#160;</div>
        <div style="text-align: center; font-variant: small-caps; font-weight: bold;">And</div>
        <div>&#160;</div>
        <div style="text-align: center; font-variant: small-caps; font-weight: bold;">Hoffmann-La Roche Inc.</div>
        <div style="text-align: center; font-variant: small-caps;"><font style="font-weight: normal;"> </font><br>
        </div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
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        <div style="text-align: center; font-weight: bold;">HTT RESEARCH, DEVELOPMENT, OPTION AND LICENSE AGREEMENT</div>
        <div>&#160;</div>
        <div style="text-align: justify; text-indent: 36pt;">This HTT RESEARCH, DEVELOPMENT, OPTION AND LICENSE AGREEMENT (the &#8220;<font style="font-weight: bold; font-style: italic;">Agreement</font>&#8221;) is entered into as of the 8<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">th</sup> day of April,
          2013 (the &#8220;<font style="font-weight: bold; font-style: italic;">Effective Date</font>&#8221;) by and among <font style="font-weight: bold; font-variant: small-caps;">Isis Pharmaceuticals, Inc.</font>, a Delaware corporation, having its principal place
          of business at 2855 Gazelle Court, Carlsbad, California 92010 (&#8220;<font style="font-weight: bold; font-style: italic;">Isis</font>&#8221;), and<font style="font-weight: bold; font-variant: small-caps;"> F. Hoffmann-La Roche Ltd</font>, a Swiss
          corporation, having its principal place of business at Grenzacherstrasse 124, 4070 Basel, Switzerland (&#8220;<font style="font-weight: bold; font-style: italic;">Roche Basel</font>&#8221;) and <font style="font-weight: bold; font-variant: small-caps;">
            Hoffmann-La Roche Inc.</font>,&#160; a New Jersey corporation, having its principal place of business at 340 Kingsland Street, Nutley, New Jersey 07110 (&#8220;<font style="font-weight: bold; font-style: italic;">Roche Nutley</font>&#8221;; Roche Basel and
          Roche Nutley are collectively referred to as &#8220;<font style="font-weight: bold; font-style: italic;">Roche</font>&#8221;). Roche and Isis each may be referred to herein individually as a &#8220;<font style="font-weight: bold; font-style: italic;">Party</font>&#8221;
          or collectively as the &#8220;<font style="font-weight: bold; font-style: italic;">Parties</font>.&#8221;&#160; Capitalized terms used in this Agreement, whether used in the singular or the plural, have the meaning set forth in <font style="font-variant: small-caps;"><u>Appendix</u></font><u> 1</u>.&#160; All attached appendices and schedules are a part of this Agreement.</div>
        <div>&#160;</div>
        <div style="text-align: center; font-weight: bold;">RECITALS</div>
        <div>&#160;</div>
        <div style="text-align: justify; text-indent: 36pt; font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;">WHEREAS</font><font style="font-size: 10pt;">, Isis has expertise in discovering and developing antisense drugs, and is
            researching compounds to identify and select a drug to treat Huntington&#8217;s Disease;</font></div>
        <div>&#160;</div>
        <div style="text-align: justify; text-indent: 36pt; font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;">WHEREAS</font><font style="font-size: 10pt;">, Roche has expertise in developing and commercializing drugs, and Roche is
            interested in researching, developing and commercializing an antisense drug to treat Huntington&#8217;s Disease;</font></div>
        <div>&#160;</div>
        <div style="text-align: justify; text-indent: 36pt; font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;">WHEREAS</font><font style="font-size: 10pt;">, Roche and Isis desire to conduct research activities to identify and select at
            least one antisense drug to treat Huntington&#8217;s Disease;</font></div>
        <div>&#160;</div>
        <div style="text-align: justify; text-indent: 36pt; font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;">WHEREAS</font><font style="font-size: 10pt;">, Roche and Isis also desire to conduct a research collaboration focused on
            discovering an antisense drug to treat Huntington&#8217;s Disease using Roche&#8217;s Brain Shuttle technology designed to deliver drugs through the blood-brain barrier;</font></div>
        <div>&#160;</div>
        <div style="text-align: justify; text-indent: 36pt; font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;">WHEREAS</font><font style="font-size: 10pt;">, the Parties anticipate they will conduct the research programs in parallel with
            and without using Roche&#8217;s Brain Shuttle technology, recognizing that Isis&#8217; non-Brain Shuttle program is further along in the research and development process, and that drugs from either or both program(s) may move forward in development based
            on emergent data and the commercial market of the individual drugs; and</font></div>
        <div>&#160;</div>
        <div style="text-align: justify; text-indent: 36pt; font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;">WHEREAS</font><font style="font-size: 10pt;">, Roche desires Isis to develop the HTT drug through completion of the initial
            Phase 1 Trial and grant Roche an option to obtain an exclusive license to develop and commercialize such drug;</font></div>
        <div>&#160;</div>
        <div style="text-align: justify; text-indent: 36pt; font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;">NOW, THEREFORE</font><font style="font-size: 10pt;">, in consideration of the respective covenants, representations, warranties
            and agreements set forth herein, the Parties hereto agree as follows:</font></div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">2</font></div>
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        </div>
        <div style="text-align: center; font-weight: bold;">ARTICLE 1.</div>
        <div style="text-align: center; font-weight: bold;">RESEARCH AND DEVELOPMENT</div>
        <div>&#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="ze2de443185b9444c957b94a74cd33190">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Overview</u></font><font style="font-size: 10pt;">.<font style="font-weight: bold;">&#160;</font>The intent of the Collaboration is for the Parties to conduct two
                    research programs in parallel focused on (i) an Isis HTT program initially centered around the research of Allele Selective Compounds and Non-Allele Selective Compounds to designate an Isis Development Candidate, and (ii) a
                    collaborative HTT program between Isis and Roche, funded by Roche, involving Roche&#8217;s proprietary technology designed to enhance delivery of molecules through the blood-brain barrier (&#8220;<font style="font-weight: bold; font-style: italic;">Brain


                      Shuttle</font>&#8221;), where the Parties will combine an Isis Compound with such Brain Shuttle technology to develop a Brain Shuttle Development Candidate. From the Effective Date until the date the Option is exercised, expires or is
                    terminated (the &#8220;<font style="font-weight: bold; font-style: italic;">Option Period</font>&#8221;), Isis will Develop and fund the initial Isis Development Candidate through the first Phase 1 Trial, and Roche will have an Option to obtain an
                    exclusive license to further Develop and Commercialize the Development Candidates. Drugs from either or both program(s) may move forward in development based on data and the commercial market of the individual drugs. If Roche exercises
                    its Option, Roche will be responsible for all further pre-clinical, clinical, regulatory, manufacturing and commercial activities related to Products. The purpose of this <u>Section 1.1</u> is to provide a high-level overview of the
                    roles, responsibilities, rights and obligations of each Party under this Agreement with regard to the R&amp;D Plans and Products, and therefore this <u>Section 1.1</u> is qualified in its entirety by the more detailed provisions of
                    this Agreement set forth below.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z62345a277ab14b74b0f9e6e08d8aaebc">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Isis Development Candidate-R&amp;D Plan</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="za6ff715127624ae1a2139c9ae891fcc9">

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              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.2.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Isis Development Candidate-R&amp;D Plan Activities</u></font><font style="font-size: 10pt;">. The Isis Development Candidate-R&amp;D Plan is attached hereto
                    as <font style="font-variant: small-caps;"><u>Appendix</u></font><u> 2</u>, and sets forth the research and development activities the Parties will conduct during the Option Period with the first Compound designated an Isis Development
                    Candidate, and through completion of the Registration-Directed Trials. As of the Effective Date, the Isis Development Candidate-R&amp;D Plan focuses primarily on the research and Development of Non-Allele Selective Compounds, and is
                    intended to achieve designation of one Isis Development Candidate and one Back-Up Compound. If the Parties subsequently decide to expand the efforts under such plan on the research and Development of Allele Selective Compounds, the
                    Parties will mutually agree on any appropriate changes to the Isis Development Candidate-R&amp;D Plan, with Roche being responsible for the incremental cost of any such changes.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z9994821d65da43d4bab29ba3ab7ffea0">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.2.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Conducting the Isis Development Candidate-R&amp;D Plan</u></font><font style="font-size: 10pt;">. During the Option Period, Roche and Isis will each use
                    Commercially Reasonable Efforts to conduct the research and Development activities designated for each of them, respectively under the Isis Development Candidate-R&amp;D Plan in accordance with the timelines specified therein, giving
                    due consideration to the recommendations and advice of the JSC; <font style="font-style: italic;">provided</font>, neither Roche nor Isis will have any obligation to perform any activity that, after having consulted the JSC, it in good
                    faith believes that continuing such activity would violate any Applicable Law, ethical principles, or principles of scientific integrity. </font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">3</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z001e2fdbe6324bf498fddf2c22822b16">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.2.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Isis&#8217; Performance Milestones</u></font><font style="font-size: 10pt;">.<font style="font-weight: bold;">&#160;</font>During the Option Period, Isis will use
                    Commercially Reasonable Efforts to:</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zbf7a8ba2b165481c9c7a8e9b2fdea934">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Designate at least one Isis Development Candidate by <font style="color: rgb(0, 0, 0);">[***]</font>; <font style="font-style: italic;">provided, however</font>, that if research or Development issues arise that are outside of Isis&#8217;
                  reasonable control and make such designation by such date impossible, the Parties will negotiate in good faith to revise the date by which Isis may designate an Isis Development Candidate;</div>
              </td>
            </tr>

        </table>
        <div>&#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="z5816df64c3024901a157dbaa7b16595a">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Within <font style="color: rgb(0, 0, 0);">[***] </font>designating an Isis Development Candidate, complete the <font style="color: rgb(0, 0, 0);">[***]</font> for such Isis Development Candidate; and</div>
              </td>
            </tr>

        </table>
        <div>&#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="zedf255d05745495db37c155c843a35fb">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(c)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Within <font style="color: rgb(0, 0, 0);">[***]</font> are completed for an Isis Development Candidate and Isis has obtained the <font style="color: rgb(0, 0, 0);">[***]</font>, <font style="color: rgb(0, 0, 0);">[***]</font>, <font style="color: rgb(0, 0, 0);">[***]</font> and <font style="color: rgb(0, 0, 0);">[***] </font>data generated from such [<font style="color: rgb(0, 0, 0);">***</font>] sufficient to support the [<font style="color: rgb(0, 0, 0);">***</font>],


                  [<font style="color: rgb(0, 0, 0);">***</font>] for such Isis Development Candidate.</div>
              </td>
            </tr>

        </table>
        <div>&#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="zc6543d2d8fc54367922ebad182d320f2">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.2.4.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Notice of Isis Development Candidate Designation</u></font><font style="font-size: 10pt;">. When Isis first designates an Isis Development Candidate, Isis
                    will notify Roche in writing promptly after such designation and, together with such notice, will provide Roche the applicable Development Candidate Data Package.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z772d05d9fa624560b922c12f80eb6a7c">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.2.5.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Isis Development Candidate IND-Enabling Toxicology Studies</u></font><font style="font-size: 10pt;">. Once available to Isis, Isis will promptly deliver to
                    Roche the pharmacology, toxicology, histology and pharmacokinetic data generated from the IND-Enabling Toxicology Studies under the Isis Development Candidate-R&amp;D Plan.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z8f75ddc35cff4889bd7bb4c8a1ddb7ea">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.2.6.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Phase 1 Trial</u></font><font style="font-size: 10pt;">. Isis will keep the JSC informed of the progress of the Phase 1 Trial. Once available to Isis, Isis
                    will promptly deliver to Roche the applicable Phase 1 Trial Data Package.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z45fc0ef8d04549d2b05d2f4864f02074">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.2.7.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>[<font style="color: rgb(0, 0, 0);">***</font>]. Prior to the Initiation of the [<font style="color: rgb(0, 0, 0);">***</font>] for the Isis Development Candidate, the Parties will discuss and mutually agree on whether to conduct an [<font style="color: rgb(0, 0, 0);">***</font>] for such Isis Development Candidate. If the Parties mutually agree to conduct such an [<font style="color: rgb(0, 0, 0);">***</font>], then the [<font style="color: rgb(0, 0, 0);">***</font>]
                  will be considered an Approved Change to the Isis Development Candidate-R&amp;D Plan and the costs to conduct such [<font style="color: rgb(0, 0, 0);">***</font>] will be treated as Additional Costs in accordance with <u>Section 1.6.1(b)</u>.</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">4</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="zcbf90c8f68984788882ecf76d093a93a">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Conducting the Brain Shuttle Development Candidate-R&amp;D Plan</u></font><font style="font-size: 10pt;">. In addition to the Isis Development
                    Candidate-R&amp;D Plan performed under <u>Section </u>1.2 above, Roche and Isis will conduct a research collaboration under the Brain Shuttle Development Candidate-R&amp;D Plan to identify a Brain Shuttle Development Candidate. The
                    Brain Shuttle Development Candidate-R&amp;D Plan is attached hereto as <font style="font-variant: small-caps;"><u>Appendix</u></font><u> 3</u> and sets forth the research activities the Parties will conduct through designation of the
                    Brain Shuttle Development Candidate. Once the first Brain Shuttle Development Candidate is designated, Roche will update the Brain Shuttle Development Candidate-R&amp;D Plan to cover Development activities for the first Brain Shuttle
                    Development Candidate through the completion of Registration-Directed Trials, which plan will be consistent with the level of effort and diligence set forth in the Isis Development Candidate-R&amp;D Plan. Changes to the Brain Shuttle
                    Development Candidate-R&amp;D Plan that affect the Isis R&amp;D Activities thereunder must be unanimously agreed to by the JSC or, if the JSC no longer exists, by the Parties. Roche and Isis will each use Commercially Reasonable Efforts
                    to conduct the research and Development activities designated for each of them, respectively under the Brain Shuttle Development Candidate-R&amp;D Plan in accordance with the timelines specified therein, giving due consideration to the
                    recommendations and advice of the JSC; <font style="font-style: italic;">provided</font>, neither Roche nor Isis will have any obligation to perform any activity that, after having consulted the JSC, it in good faith believes that
                    continuing such activity would violate any Applicable Law, ethical principles, or principles of scientific integrity.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zcef2e50dcf37488ea04897c67dadd30a">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.3.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Brain Shuttle Development Candidate Designation</u></font><font style="font-size: 10pt;">. If Roche, after consultation with the JSC, determines a Compound <font style="color: rgb(0, 0, 0);">under the Brain Shuttle Development Candidate-R&amp;D Plan</font> is ready to start IND-Enabling Toxicology Studies, such Compound will be a &#8220;<font style="font-weight: bold; font-style: italic;">Brain
                      Shuttle Development Candidate</font>.&#8221;</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z34f91d0e5cb1438cb9634dcee5936170">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.3.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Brain Shuttle Development Candidate IND-Enabling Toxicology Studies</u></font><font style="font-size: 10pt;">. Once available to Roche, Roche will promptly
                    deliver to Isis the pharmacology, toxicology, histology and pharmacokinetic data generated from the IND-Enabling Toxicology Studies under the Brain Shuttle Development Candidate-R&amp;D Plan.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z5f053de610654991afebb474acb0fd4b">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.3.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Phase 1 Trial</u></font><font style="font-size: 10pt;">. Roche will use Commercially Reasonable Efforts to conduct the Phase 1 Trial for the Brain Shuttle
                    Development Candidate under the Brain Shuttle Development Candidate-R&amp;D Plan. Roche will keep Isis informed of the progress of each Phase 1 Trial through the JSC.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zaaec834c0bee444da8e01f956a2fb112">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.4.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Disclosure of Results</u></font><font style="font-size: 10pt;">. Each Party will promptly disclose to the other Party via disclosure at JSC meetings the
                    results of work performed by such Party under each R&amp;D Plan. Isis and Roche will provide reports and analyses at each JSC meeting, and more frequently on reasonable request by the JSC, detailing the current status of each R&amp;D
                    Plan. If the JSC has dissolved, then each Party will promptly disclose such data and results directly to the other Party.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">5</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
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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="zc5ab01b9681a416eb800f065460d6c66">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.5.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Development Management</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z47587c8bc9da40179a64ba5e4d6e0366">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.5.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>JSC</u></font><font style="font-size: 10pt;">. The Parties will establish a joint steering committee (the &#8220;<font style="font-weight: bold; font-style: italic;">JSC</font>&#8221;) to provide advice and make recommendations on the conduct of the Collaboration consistent with the R&amp;D Plans. The JSC will act as a forum for sharing information about the activities conducted by the Parties
                    hereunder, as an advisory body, and will have decision-making authority to the extent set forth on <u><font style="font-variant: small-caps;">Schedule</font>&#160;1.5.1</u>. The JSC will consist of two (2) qualified representatives
                    appointed by Isis, and two (2) qualified representatives appointed by Roche. Prior to Option exercise, Isis will designate one of its representatives to act as the chairperson of the JSC. After Option exercise, Roche will designate one
                    of its representatives to act as the chairperson of the JSC. The chairperson will be responsible for overseeing the activities of the JSC. <u><font style="font-variant: small-caps;">Schedule</font>&#160;1.5.1</u> sets forth certain JSC
                    governance matters. The JSC will determine the JSC operating procedures at its first meeting, which will be codified in the written minutes of the first JSC meeting. In addition, during the term of the JSC, CHDI will have the right to
                    participate in JSC meetings as a non-voting observer; <font style="font-style: italic;">provided, however</font>, if Isis and Roche reasonably determine in good faith after discussion with CHDI that, due to participation in programs
                    with a potentially competitive drug, CHDI should no longer participate in JSC meetings and be exposed to program data, then Isis will provide CHDI with written notice of such determination and thereafter CHDI will no longer participate
                    in meetings of the JSC. The CHDI observer shall be a person reasonably acceptable to both Roche and Isis.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zc85e3d95aba54e56b17285033f598c6f">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.5.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Decision Making</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z3070a5eaa0eb4879835bb550bc27d590">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Under the Isis Development Candidate-R&amp;D Plan</u></font><font style="font-size: 10pt;">. Prior to Option exercise, except as provided
                    below in <u>Section 1.5.2(b)</u>, Isis will have the final decision-making authority regarding the conduct of the Isis Development Candidate-R&amp;D Plan, and whether to accept and how to implement the JSC&#8217;s recommendations.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z918505dec3724facb2bbcd94a7dfa950">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>With Respect to All Subsequent Isis Development Candidates</u></font><font style="font-size: 10pt;">. For the second and any subsequent
                    Isis Development Candidates, subject to <u>Section 1.5.2(e)</u>, Roche will have the final decision-making authority regarding whether to Initiate the IND-Enabling Toxicology Studies and all subsequent Development activities
                    thereafter. If the first Compound designated an Isis Development Candidate is no longer being Developed, then the next Compound designated an Isis Development Candidate that takes its place will still be considered the &#8220;first&#8221; Isis
                    Development Candidate for purposes of this <u>Section 1.5.2(b)</u>, and the Isis Development Candidate-R&amp;D Plan will be amended accordingly as mutually agreed by the Parties to cover any research and Development activities and
                    related costs for such replacement Isis Development Candidate in accordance with <u>Section 1.8</u> below.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z8f0f8f0bf9e44d92b6ede73995452713">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(c)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Under the Brain Shuttle Development Candidate-R&amp;D Plan</u></font><font style="font-size: 10pt;">. Subject to <u>Section 5.1</u> and
                    <u>Section 1.5.2(e)</u>, Roche will have the final decision-making authority regarding selection of Brain Shuttle Development Candidates, the conduct of the Brain Shuttle Development Candidate-R&amp;D Plan, and whether to accept and how
                    to implement the JSC&#8217;s recommendations.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">6</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="zcd725cde30a746979f5ed2fe11f73da5">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(d)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Development Decision Making After Option Exercise</u></font><font style="font-size: 10pt;">. After Option exercise and without limiting
                    Roche&#8217;s obligations under this Agreement to use Commercially Reasonable Efforts, Roche will have the final decision making authority for which Products to Initiate Phase 2 and all subsequent Clinical Trials. In addition, Roche will have
                    full responsibility for designing, conducting, funding and implementing the further Development of Products, including clinical trials and regulatory submissions.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div>&#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="za32e73a936dd4bd5ae2b961dcfccd700">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(e)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Exceptions</u></font><font style="font-size: 10pt;">. If Roche&#8217;s exercise of its decision-making authority pursuant to <u>Section
                      1.5.2(b)</u>, <u>Section 1.5.2(c)</u> or <u>Section 1.5.2(d)</u> would increase costs for any Isis R&amp;D Activities, then such decision must be unanimously agreed to by the JSC or, if the JSC no longer exists, by the Parties.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zcaad982dbb3943aab7c103e95414612f">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.5.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Alliance Managers</u></font><font style="font-size: 10pt;">. 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;). Each Alliance Manager will be responsible for supporting the JSC and performing the activities listed in <u><font style="font-variant: small-caps;">Schedule</font>&#160;1.5.3</u>.&#160;


                    &#160;&#160; </font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z30f260e5ae0e4af7b86036326fb7f466">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.6.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Collaboration Costs and Expenses</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z10a0c39d2b60497a81011e7ac41ea8a0">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.6.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Isis Development Candidate-R&amp;D Plan</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z6096dd9c11124bad8e85d5418ec068c2">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Isis Development Candidate-R&amp;D Plan Costs &#8211; Generally</u></font><font style="font-size: 10pt;">. During the Option Period, except as otherwise provided
                    under <u>Section 1.6.1(b)</u>, Isis will be responsible for all costs and expenses associated with the Isis R&amp;D Activities designated under the Isis Development Candidate-R&amp;D Plan for the first Compound designated an Isis
                    Development Candidate, and Roche will be responsible for all costs and expenses associated with any Roche R&amp;D Activities designated under the Isis Development Candidate-R&amp;D Plan. Isis cannot change any of the Roche R&amp;D
                    Activities without the unanimous agreement of the JSC or, if the JSC no longer exists, Roche. As provided in <u>Section 1.8</u>, Roche is responsible for the costs of any research and Development activities for an Additional Isis
                    Development Candidate.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="ze8f5c076d2c542a58f78c64f98811940">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Additional Costs Associated with Approved Changes to the Isis Development Candidate-R&amp;D Plan</u></font><font style="font-size: 10pt;">. Roche will be
                    responsible for paying Isis quarterly in advance for any Additional Costs resulting from Approved Changes. Roche will review and approve the Additional Costs before any Approved Changes are implemented by Isis. Isis and Roche will
                    update the Isis Development Candidate-R&amp;D Plan to reflect any such Approved Changes and Isis will invoice Roche for any such Additional Costs quarterly in advance after such Additional Costs are approved. Isis may reasonably
                    estimate its FTE time required to perform the Approved Changes. Roche will pay the invoices submitted pursuant to this <u>Section 1.6.1(b)</u> for such approved Additional Costs within thirty (30) days after Roche&#8217;s receipt of the
                    applicable invoice. Isis will use its Commercially Reasonable Efforts to complete Approved Changes within the amount of the agreed Additional Costs. If at any time during the performance of the Approved Changes, Isis expects its actual
                    Additional Costs to be greater than [<font style="color: rgb(0, 0, 0);">***</font>] of the previously agreed Additional Costs for a particular Approved Change(s) (the difference being &#8220;<font style="font-weight: bold; font-style: italic;">Change Overruns</font>&#8221;), then Isis shall promptly notify the JSC which will then discuss and agree whether the Approved Changes should continue, and if so, how the Parties shall share the cost of any Change Overruns. Any
                    Change Overruns Roche agrees to pay will be considered Additional Costs. Unless approved by Roche, Roche will not be responsible for Change Overruns that are greater than [<font style="color: rgb(0, 0, 0);">***</font>] of the previously
                    agreed Additional Costs for a particular Approved Change(s).</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">7</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z15c5e86500ec4f4686c439b494a9edb1">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(c)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Reconciliation of Any Overpayment or Underpayment of Additional Costs</u></font><font style="font-size: 10pt;">. At the end of every second (2<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">nd</sup>)
                    and fourth (4<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">th</sup>) Calendar Quarter during any period where Additional Costs are incurred (and again at the completion of all of the Approved Changes), Isis will provide Roche with an accounting of actual costs incurred by Isis
                    (including Isis&#8217; estimated FTE costs) compared to the Additional Costs paid in advance by Roche. After such accounting, if Isis&#8217; actual costs incurred were greater than the Additional Costs paid in advance by Roche, then Roche will pay
                    Isis the amount of such difference within thirty (30) days after Isis provides the accounting to Roche and Roche&#8217;s receipt of an invoice from Isis. If, however, after such accounting Isis&#8217; actual costs incurred were less than the
                    Additional Costs paid in advance by Roche, then Isis will provide Roche the amount of such difference in the form of a credit against the next payment (including any future payments for any then ongoing Approved Changes) to be paid by
                    Roche to Isis under this Agreement.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z0fe3439adfc44d6a9bfb6b6d8ff7ef2c">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.6.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Brain Shuttle Development Candidate-R&amp;D Plan</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zdffa18e39f8f4767b28f141db433ede6">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Brain Shuttle Development Candidate-R&amp;D Plan Costs</u></font><font style="font-size: 10pt;">. Roche will be responsible for all costs and expenses
                    associated with the Brain Shuttle Development Candidate-R&amp;D Plan, including pre-clinical <font style="font-style: italic;">in vitro</font> or <font style="font-style: italic;">in vivo</font> efficacy studies costs, manufacturing
                    costs, IND-Enabling Toxicology Study costs, chronic toxicology study costs, clinical trial costs (including OLE Trial costs), and all costs and expenses associated with the Isis R&amp;D Activities and the Roche R&amp;D Activities
                    designated under the Brain Shuttle Development Candidate-R&amp;D Plan.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">8</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z45ac2d6433bf4a8ea15daa8f487d1552">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Brain Shuttle Development Candidate-R&amp;D Plan &#8211; Cost Estimates and Invoicing</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zecad0cb5c3dd4cf9aa3f0795c7181b71">

            <tr>
              <td style="width: 108pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(i)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Brain Shuttle Program Cost Estimate</u></font><font style="font-size: 10pt;">. Roche will pay Isis in advance on a quarterly basis for
                    Isis&#8217; performance of the Isis R&amp;D Activities designated under the Brain Shuttle Development Candidate-R&amp;D Plan to progress to the next significant stage of research or development at the then-applicable Isis FTE Rate, plus any
                    reasonable out-of-pocket expenses incurred by Isis in performing such work. The costs of ASOs to be supplied by Isis under the Brain Shuttle Development Candidate-R&amp;D Plan will be calculated in accordance with <u><font style="font-variant: small-caps;">Schedule</font>&#160;1.6.2(b)(i)</u>. Isis may reasonably estimate its FTE time required to perform the Isis R&amp;D Activities designated under the Brain Shuttle Development Candidate-R&amp;D Plan. Each
                    time the Parties agree to, or expand, the Isis R&amp;D Activities under the Brain Shuttle Development Candidate-R&amp;D Plan, Isis will provide Roche with a good faith estimate of the internal and external costs (each such estimate, a &#8220;<font style="font-weight: bold; font-style: italic;">Brain Shuttle Program Cost Estimate</font>&#8221;) to conduct such Isis R&amp;D Activities to the end of the next significant stage of research or development, and Isis and Roche will endeavor
                    to mutually agree on a final Brain Shuttle Program Cost Estimate.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="ze6dada14040c4d248f992088f67c5776">

            <tr>
              <td style="width: 108pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(ii)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Payment Schedule and Invoicing; Reconciliation of Any Overpayment or Underpayment of Additional Costs</u></font><font style="font-size: 10pt;">. Once a given Brain Shuttle Program Cost Estimate is finalized under <u>Section 1.6.2(b)(i)</u> and Isis is ready to start such work, Isis will deliver to Roche each quarter in advance an invoice for Isis&#8217; estimated costs for
                    the coming Calendar Quarter. Roche will pay Isis within thirty (30) days after receiving such invoice. Isis will use its Commercially Reasonable Efforts to complete the Isis R&amp;D Activities related to a given Brain Shuttle Program
                    Cost Estimate within the amount of the agreed Brain Shuttle Program Cost Estimate. For each Brain Shuttle Program Cost Estimate, Isis and Roche will handle any cost overruns and reconciliations of any overpayment or underpayment of
                    Additional Costs using the same process used under <u>Section 1.6.1(b)</u> and <u>Section 1.6.1(c)</u> above.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z6a3e1a2ed6974791bc353f50c74454d0">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.7.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Manufacturing and Supply</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z7ac2cdb480eb4fefb9d0b62ede2ccea0">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.7.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Isis Development Candidate-R&amp;D Plan</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z39f44dfb9c5143b4bdc8a7d053ab7275">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Supplies for Activities During the Option Period</u></font><font style="font-size: 10pt;">. During the Option Period, [<font style="color: rgb(0, 0, 0);">***</font>],


                    for the first Compound designated an Isis Development Candidate, Isis will supply API, finished Product and any research-grade Compound sufficient to support the Isis R&amp;D Activities designated under the Isis Development
                    Candidate-R&amp;D Plan. In addition, during the Option Period, for the first Compound designated an Isis Development Candidate, Isis will supply API, finished Product, and research-grade Compound sufficient to support any Roche R&amp;D
                    Activities designated under the Isis Development Candidate-R&amp;D Plan, and Isis will provide Roche with such API and finished Product [<font style="color: rgb(0, 0, 0);">***</font>].</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">9</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z933b852233f14c2fa105c06fd59ab928">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Supplies for Activities After Option Exercise</u></font><font style="font-size: 10pt;">. After Option exercise, Isis will deliver to Roche, if Roche desires,
                    any inventory of cGMP API, non-GMP API, radiolabeled material, GMP and non-GMP finished Product, packaged clinical trial material, and non-GMP packaged trial material containing the Isis Development Candidate in Isis&#8217; possession [<font style="color: rgb(0, 0, 0);">***</font>].</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zca9a9191c8774d42abc3027d7de7c352">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.7.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Supplies for Activities under the Brain Shuttle Development Candidate-R&amp;D Plan</u></font><font style="font-size: 10pt;">. The Parties will mutually agree
                    on the quantity of API and research-grade Compound needed to support the Isis R&amp;D Activities and Roche R&amp;D Activities designated under the Brain Shuttle Development Candidate-R&amp;D Plan. Roche will be responsible for all costs
                    and expenses associated with supply of research-grade Compound, API and finished Product under the Brain Shuttle Development Candidate-R&amp;D Plan.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z035e9fde37294e7b841e96de88b34e9e">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.8.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Requests to Work on an Additional Isis Development Candidate</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z0491ed815ecb47579bba2005d1b4d35b">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.8.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Requests During the Option Period</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="ze6b189ba6655446584655fe78aa49547">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>If, during the Option Period, Roche provides Isis a written request to discover and Develop a replacement or second Isis Development Candidate (&#8220;<font style="font-weight: bold; font-style: italic;">Additional Isis Development Candidate</font>&#8221;),


                  Isis will use Commercially Reasonable Efforts to perform such work under a mutually agreed amendment to the Isis Development Candidate-R&amp;D Plan. The cost to perform such work leading up to the IND-Enabling Toxicology Studies will be
                  paid by Roche in accordance with <u>Section 1.8.3</u> below.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z08ec7f9c7aaa405ab21623938ab306be">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>If, during the Option Period, Roche provides Isis a written request to perform the IND-Enabling Toxicology Studies for the Additional Isis Development Candidate, Isis will use Commercially Reasonable Efforts to perform such work under
                  a mutually agreed amendment to the Isis Development Candidate-R&amp;D Plan. If the first Compound designated an Isis Development Candidate is being Developed under this Agreement when Isis receives such written request from Roche, then in
                  lieu of Isis&#8217; actual costs to conduct the IND-Enabling Toxicology Studies on such Additional Isis Development Candidate, Roche shall pay Isis [<font style="color: rgb(0, 0, 0);">***</font>]. If, however, the first Compound designated an
                  Isis Development Candidate has already completed IND-Enabling Toxicology Studies but is no longer being Developed under this Agreement when Isis receives such written request from Roche, then the [<font style="color: rgb(0, 0, 0);">***</font><u>]</u>
                  shall NOT be paid by Roche. Instead, Isis&#8217; [<font style="color: rgb(0, 0, 0);">***</font>] to conduct the IND-Enabling Toxicology Studies for the Additional Isis Development Candidate will be paid by Roche in accordance with <u>Section
                    1.8.3</u> below.</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">10</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="zb3cd68b783064e72b813c47f45e2a34a">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.8.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Requests After Option Exercise</u></font><font style="font-size: 10pt;">. If, after Option exercise, Roche provides Isis a written
                    request to discover an Additional Isis Development Candidate, then Isis will use Commercially Reasonable Efforts to discover an Additional Isis Development Candidate under a mutually agreed amendment to the Isis Development
                    Candidate-R&amp;D Plan, and once such Additional Isis Development Candidate is designated, Roche will be responsible for conducting the IND-Enabling Toxicology Studies for such Additional Isis Development Candidate. The cost to perform
                    the work to discover an Additional Isis Development Candidate will be paid by Roche in accordance with <u>Section 1.8.3</u> below. Roche&#8217;s right to request Isis to perform the work described in this <u>Section 1.8.2</u> expires [<font style="color: rgb(0, 0, 0);">***</font>], or if [<font style="color: rgb(0, 0, 0);">***</font>] but in no case later than [<font style="color: rgb(0, 0, 0);">***</font>] days after the [<font style="color: rgb(0, 0, 0);">***</font>].</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="za9248505b76c4177aafce01978e6bf5d">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.8.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Additional Isis Development Candidate-Cost Estimate - Payment Mechanics</u></font><font style="font-size: 10pt;">. Before Isis starts any
                    work requested under <u>Section 1.8.1(a)</u>, <u>Section 1.8.1(b)</u> (if applicable), or <u>Section 1.8.2</u>, the Parties will finalize (via the JSC) a mutually agreed cost estimate covering Isis&#8217; estimate of its [<font style="color: rgb(0, 0, 0);">***</font>] by Isis in performing such work (including the cost of API and finished Product) (the &#8220;<font style="font-weight: bold; font-style: italic;">Additional Isis Development Candidate-Cost Estimate</font>&#8221;).


                    Before Isis commences any such work, Isis will provide the JSC with a good faith estimate of the cost for Isis to conduct and complete such work, and the JSC will discuss and unanimously agree on a final Additional Isis Development
                    Candidate-Cost Estimate for Isis to conduct such activities. Isis will invoice Roche and Roche will pay Isis the Additional Isis Development Candidate-Cost Estimate using the same payment mechanism and schedule used under <u>Section
                      1.6.1(b)</u> and <u>Section 1.6.1(c)</u> above for Additional Costs.<br>
                  </font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zf051e1b64c0b49389f6c43a12be14a4e">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.9.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Subcontracting</u></font><font style="font-size: 10pt;">. Each Party may engage Third Party subcontractors to perform certain of its obligations under this
                    Agreement. Any subcontractor engaged to perform a Party&#8217;s obligations under this Agreement will meet the qualifications typically required by such Party for the performance of work similar in scope and complexity and will execute such
                    Party&#8217;s standard nondisclosure agreement. Any Party engaging a subcontractor hereunder will remain responsible for such activities.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z01f4a8d4b18b45b2978879d44a05d9e7">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.10.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Materials Transfer</u></font><font style="font-size: 10pt;">. To facilitate the activities under an R&amp;D Plan, either Party may provide certain materials
                    for use by the other Party. All such materials will be used by the receiving Party in accordance with terms of this 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 except with the written consent of the supplying Party. Except as expressly set forth herein, THE MATERIALS ARE PROVIDED &#8220;AS IS&#8221; AND WITHOUT ANY REPRESENTATION OR
                    WARRANTY, EXPRESS OR IMPLIED, INCLUDING ANY IMPLIED WARRANTY OF MERCHANTABILITY OR OF FITNESS FOR ANY PARTICULAR PURPOSE OR ANY WARRANTY THAT THE USE OF THE MATERIALS WILL NOT INFRINGE OR VIOLATE ANY PATENT OR OTHER PROPRIETARY RIGHTS
                    OF ANY THIRD PARTY.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zc44382139cab47de8f13b6cf36a8273f">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.11.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Applicable Laws</u></font><font style="font-size: 10pt;">. Each Party will perform its activities pursuant to this Agreement in compliance with good
                    laboratory and clinical practices and 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.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">11</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z6591ef45947c40ebb25d219f47013f8f">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.12.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Failure to Designate an Isis Development Candidate</u></font><font style="font-size: 10pt;">. If, despite Isis&#8217; Commercially Reasonable Efforts, by the [<font style="color: rgb(0, 0, 0);">***</font>] anniversary of the Effective Date, Isis has not designated an Isis Development Candidate, then, notwithstanding any provision to the contrary in this Agreement (i) work under the Isis
                    Development Candidate-R&amp;D Plan will stop; (ii) the Parties&#8217; will no longer have an obligation to perform any activities under this <u>ARTICLE 1</u> with respect to the Isis Development Candidate-R&amp;D Plan; (iii) the Parties&#8217;
                    respective obligations and Roche&#8217;s rights under this Agreement with respect to the Isis Development Candidate-R&amp;D Plan and any related Compounds will then terminate; (iv) Isis will have exclusive rights (and Roche will, and hereby
                    does grant Isis an exclusive license) to all data, results and information generated under the Isis Development Candidate-R&amp;D Plan, and Roche will promptly transfer to Isis copies of all such data, results and information in Roche&#8217;s
                    possession; and (v) Roche will and hereby does grant Isis an irrevocable, royalty-free, non-exclusive license to any Know-How and/or Patent Rights generated by Roche under the Isis Development Candidate-R&amp;D Plan to research,
                    develop, manufacture and commercialize ASOs designed to bind to the RNA encoding HTT. Isis will control any Jointly-Owned Collaboration Patents that resulted from the Isis Development Candidate-R&amp;D Plan, and Roche will assign
                    ownership to Isis on condition that Isis grants Roche an irrevocable, royalty-free, non-exclusive license for any purpose (other than researching, developing, manufacturing or commercializing products comprising an ASO).</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z7d38a5dd2e0846a3973c90b1546e52ee">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">1.13.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Failure to Designate a Brain Shuttle Development Candidate</u></font><font style="font-size: 10pt;">. If, despite the Parties&#8217; Commercially Reasonable
                    Efforts, by the [<font style="color: rgb(0, 0, 0);">***</font>] anniversary of the Effective Date, Roche has not designated a Brain Shuttle Development Candidate, then, notwithstanding any provision to the contrary in this Agreement (i)
                    work under the Brain Shuttle Development Candidate-R&amp;D Plan will stop; (ii) the Parties&#8217; will no longer have an obligation to perform any activities under this <u>ARTICLE 1</u> with respect to the Brain Shuttle Development
                    Candidate-R&amp;D Plan; and (iii) the Parties&#8217; respective obligations and Roche&#8217;s rights under this Agreement with respect to the Brain Shuttle Development Candidate-R&amp;D Plan and any related Compounds will then terminate.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">12</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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;">ARTICLE 2.</div>
        <div style="text-align: center; font-weight: bold;">EXCLUSIVITY COVENANTS</div>
        <div>&#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="zd61c88fb19244f2ca245ca71e5925aae">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">2.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Exclusivity</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z7553f9b43e7d4785ac3cdd0e49b210d7">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">2.1.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; color: rgb(0, 0, 0);"><u>Exclusivity Covenants</u></font><font style="font-size: 10pt; color: rgb(0, 0, 0);">.</font><font style="font-size: 10pt;"> Each Party
                    agrees that, except in the performance of its obligations or exercise of its rights under this Agreement, and except as set forth in <u>Section 2.1.2</u> or <u>Section 2.1.3</u>:</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z394ad9b07bc646698a0eefb9bbd272d3">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>The Parties&#8217; Exclusivity Covenants During the Option Period</u></font><font style="font-size: 10pt;">. During the Option Period, each Party will work
                    exclusively within the collaboration described in the Agreement to conduct all discovery, research, development, manufacture or commercialization of an ASO that is designed to bind to the RNA that encodes HTT in the Field.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zae832c818c9f410c9cd186df74caa12c">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>The Parties&#8217; Exclusivity Covenants After Option Exercise</u></font><font style="font-size: 10pt;">. After Option exercise:</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z0d6cc377ccaf4aec9b762288543c03df">

            <tr>
              <td style="width: 108pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(i)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Developing an NAS Development Candidate</u></font><font style="font-size: 10pt;">. If Roche is Developing or Commercializing a
                    Development Candidate comprising a Non-Allele Selective Compound (an &#8220;<font style="font-weight: bold; font-style: italic;">NAS Development Candidate</font>&#8221;), then until the Full Royalty Period ends in the first Major Market, neither
                    Party nor any of its Affiliates or Sublicensees will sell an ASO approved by a Regulatory Authority for marketing and sale that is designed to bind to the RNA that encodes HTT in the Field. After the end of the Full Royalty Period in
                    the first Major Market, the exclusivity covenants will continue on a country-by-country basis in each country where the Full Royalty Period still applies [<font style="color: rgb(0, 0, 0);">***</font>].</font>
                  <div style="font-size: 10pt;"><br>
                  </div>
                  <font style="font-size: 10pt;">If, during the Reduced Royalty Period for such NAS Development Candidate, Isis (on its own or with a Third Party) following marketing approval sells an ASO designed to bind to the RNA that encodes HTT in the
                    Field, then [<font style="color: rgb(0, 0, 0);">***</font>] and Roche&#8217;s worldwide license under <u>Section 4.1.1</u> solely with respect to such NAS Development Candidate will [<font style="color: rgb(0, 0, 0);">***</font>]; or</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">13</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z6ca31fee46a74a288b0f9a1116f46dd0">

            <tr>
              <td style="width: 108pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(ii)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Developing an AS Development Candidate</u></font><font style="font-size: 10pt;">. If (and for as long as) Roche is Developing or
                    Commercializing a Development Candidate comprising an Allele Selective Compound (an &#8220;<font style="font-weight: bold; font-style: italic;">AS Development Candidate</font>&#8221;), then through [<font style="color: rgb(0, 0, 0);">***</font>]
                    prior to the anticipated end of the Full Royalty Period in the relevant country, neither Party nor any of its Affiliates or Sublicensees will file an NDA, MAA or JNDA, as applicable, for an ASO that is designed to bind to an SNP site
                    within an HTT RNA associated with an expanded CAG repeat to selectively reduce the expanded CAG-repeat containing RNA relative to the normal HTT RNA (each such ASO, an &#8220;<font style="font-weight: bold; font-style: italic;">AS ASO</font>&#8221;);


                    <font style="font-style: italic;">provided, however</font>, that if within [<font style="color: rgb(0, 0, 0);">***</font>] for such AS Development Candidate but in no case later than [<font style="color: rgb(0, 0, 0);">***</font>],
                    Roche does not request Isis to research and develop a second AS Development Candidate designed for use in a patient population substantially different from the patient population for the AS Development Candidate being developed or
                    commercialized by Roche (as determined by genetic testing) (or if Roche later stops Developing or Commercializing such AS ASO), then, subject to the potential [<font style="color: rgb(0, 0, 0);">***</font>], Isis, its Affiliates or
                    Sublicensees may sell AS ASOs designed for use in a patient population substantially different from the patient population for the AS Development Candidate being developed or commercialized by Roche (as determined by [<font style="color: rgb(0, 0, 0);">***]</font>) where [<font style="color: rgb(0, 0, 0);">***</font>] (Y) [<font style="color: rgb(0, 0, 0);">***</font>], or (Z) [<font style="color: rgb(0, 0, 0);">***</font>].</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z317c5e550bd8491e9c6cc3182cb01942">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">2.1.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; color: rgb(0, 0, 0);"><u>Limitations and Exceptions to </u></font><font style="font-size: 10pt; font-weight: bold;"><u>Isis</u></font><font style="font-size: 10pt; font-weight: bold; color: rgb(0, 0, 0);"><u>&#8217; Exclusivity Covenants</u></font><font style="font-size: 10pt; color: rgb(0, 0, 0);">.</font><font style="font-size: 10pt; font-weight: bold; color: rgb(0, 0, 0);">&#160;</font><font style="font-size: 10pt;">Notwithstanding anything to the contrary in this Agreement, Isis&#8217; practice of the following will not violate <u>Section 2.1.1</u>:</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zb7a5123048d44b6c8fe02982e43d4d62">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Performance of the Isis R&amp;D Activities;</div>
              </td>
            </tr>

        </table>
        <div>&#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="z2506b49ebd42409e85a3cdee64b8c30f">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Any activities pursuant to the Prior Agreements as in effect on the Effective Date; and</div>
              </td>
            </tr>

        </table>
        <div>&#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="z43cb2ddf3cd346a5a92a455bda7d510e">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(c)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>The granting of, or performance of obligations or exercise of rights under, Permitted Licenses.</div>
              </td>
            </tr>

        </table>
        <div>&#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="ze5f106963a464fecadd3dba6a8e11431">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">2.1.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Limitations and Exceptions to Roche&#8217;s Exclusivity Covenants</u></font><font style="font-size: 10pt;">.&#160; Notwithstanding anything to the contrary in this
                    Agreement, Roche&#8217;s performance of the Roche R&amp;D Activities will not violate <u>Section 2.1.1</u>.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="za3f1b8f3eb0e4a429abd6513b186c822">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">2.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; color: rgb(0, 0, 0);"><u>Effect of Exclusivity on Indications</u></font><font style="font-size: 10pt; color: rgb(0, 0, 0);">. Isis and Roche are subject to
                    certain exclusivity covenants under <u>Section </u></font><font style="font-size: 10pt;">2.1</font><font style="font-size: 10pt; color: rgb(0, 0, 0);">; </font><font style="font-size: 10pt; font-style: italic; color: rgb(0, 0, 0);">however</font><font style="font-size: 10pt; color: rgb(0, 0, 0);">, the Parties acknowledge and agree that each Party (on its own or with a Third Party) may pursue products for any indication that are not designed to bind to the RNA that encodes HTT (or
                    designed to selectively reduce HTT RNA alleles containing expanded CAG repeats), even if such products treat Huntington&#8217;s Disease.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">14</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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;">ARTICLE 3.</div>
        <div style="text-align: center; font-weight: bold;">EXCLUSIVE OPTION</div>
        <div>&#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="z10252116bd7a4f9d9d657f0ca4c3cfa6">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">3.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Option and Option Deadline</u></font><font style="font-size: 10pt;">. Isis hereby grants Roche an exclusive option to obtain the license set forth in <u>Section


                      4.1.1</u> (the &#8220;<font style="font-weight: bold; font-style: italic;">Option</font>&#8221;). To obtain the license set forth in <u>Section 4.1.1</u>, Roche must exercise the Option by the earlier of the following (the &#8220;<font style="font-weight: bold; font-style: italic;">Option Deadline</font>&#8221;): (i) the [<font style="color: rgb(0, 0, 0);">***</font>] following Roche&#8217;s receipt of the Phase 1 Trial Data Package from Isis under <u>Section 1.2.6</u> for the
                    first Phase 1 Trial with an Isis Development Candidate (as such Phase 1 Trial is described in the Isis Development Candidate R&amp;D Plan or as may otherwise be modified by the JSC); or (ii) [<font style="color: rgb(0, 0, 0);">***</font>]
                    the Phase 1 Trial Data Package is available in the first Phase 1 Trial for a Brain Shuttle Development Candidate but in no case later than [<font style="color: rgb(0, 0, 0);">***</font>] after the last patient receives his/her last dose
                    in such Phase 1 Trial; or (iii) [<font style="color: rgb(0, 0, 0);">***</font>].</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="ze05f62125cad455ab8516c123e873785">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">3.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Option Exercise; Option Expiration</u></font><font style="font-size: 10pt;">. If, by the Option Deadline, Roche (i) notifies Isis in writing that it is
                    exercising the Option, and (ii) thereafter, Roche timely pays Isis the license fee set forth in <u>Section 6.3</u>, Isis will, and hereby does, grant Roche the license set forth in <u>Section 4.1.1</u>. Prior to the Option Deadline,
                    Roche shall have the full opportunity to conduct due diligence to evaluate whether to exercise the Option and Isis shall cooperate with Roche and to ensure that all necessary data and information, including clinical and manufacturing
                    data and any available [<font style="color: rgb(0, 0, 0);">***</font>] analysis, are provided to Roche. If, by the Option Deadline, Roche has not provided Isis a written notice stating that Roche is exercising its Option, and within
                    thirty (30) days after providing such notice paid Isis the license fee set forth in <u>Section 6.3</u>, then Roche&#8217;s Option will expire. If Roche&#8217;s Option expires then <u>Section 10.4.1</u> and <u>Section 10.4.2</u> will apply.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z04c203ad13ab4df59fd9d75a6ed6f3df">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">3.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>HSR</u></font><font style="font-size: 10pt;">.<font style="font-weight: bold;">&#160;</font>If, by the Option Deadline, Roche notifies Isis in writing that it is
                    exercising the Option, each Party shall (i) cooperate with the other Party in the preparation, execution and filing of all documents that may be required pursuant to the HSR Act or any other Applicable Law, and (ii) observe all
                    applicable waiting periods before consummating the Option Exercise as set forth in <u>Section 3.2</u>.&#160; Each Party shall bear its own costs (including counsel or other expert fees) with respect to preparing, executing and filing such
                    documents.&#160; Subject to the terms and conditions of this Agreement, each Party shall use all reasonable efforts to take, or cause to be taken, all reasonable actions and to do, or cause to be done, all things necessary and appropriate to
                    consummate the exercise of the Option contemplated by <u>Section 3.2</u> of this Agreement, should Roche choose to exercise the Option.&#160; Notwithstanding anything to the contrary contained in this Agreement, Roche shall have the sole
                    and exclusive right to determine, at its discretion but without any obligation whatsoever, whether it shall have any obligation to take any actions in connection with, or agree to, any demands for the license, sale, divestiture or
                    disposition of assets of Roche or its Affiliates or Isis, asserted by the United States Federal Trade Commission, the Antitrust Division of the United States Department of Justice or any other Regulatory Authority in connection with
                    antitrust matters or international competition laws, or to defend through litigation any proceeding commenced by the Federal Trade Commission, the Antitrust Division of the United States Department of Justice or other Governmental
                    Authority in connection with the foregoing matters.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">15</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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;">ARTICLE 4.</div>
        <div style="text-align: center; font-weight: bold;">LICENSE GRANTS</div>
        <div>&#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="za55c5ddc90344c19a125c4c52235a43d">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">4.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>License Grants; Sublicense Rights</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z8ec407a134294661b97e66bf4b1367c2">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">4.1.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Development and Commercialization License Grant to Roche</u></font><font style="font-size: 10pt;">. Subject to the terms of this Agreement, effective upon
                    Roche&#8217;s exercise of the Option in accordance with this Agreement, Isis grants to Roche a worldwide, exclusive, royalty-bearing, sublicensable (in accordance with <u>Section 4.1.4</u> below) license under the Licensed Technology to
                    research, Develop, Manufacture, have Manufactured (in accordance with <u>Section 4.1.4</u> below) and Commercialize Products in the Field.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z3a713d4765e746b8bbc6ac66a95197bb">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">4.1.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Brain Shuttle IP Licenses</u></font><font style="font-size: 10pt;">. As further specified in <u>Section 7.1.3</u>, the Joint Patent Committee will classify
                    the Brain Shuttle Collaboration Patents into the following sub-categories: (w) Brain Shuttle-Specific Collaboration Patents, (x) ASO-Specific Collaboration Patents, (y) Linker-Specific Collaboration Patents, and (z) Omnibus
                    Collaboration Patents. With respect to each such sub-category of Brain Shuttle Collaboration Patents, the Parties grant one another the following licenses:</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z4bd4a2b815874042978274ea13e898de">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Licenses to Roche to Brain Shuttle Collaboration Patents</u></font><font style="font-size: 10pt;">. Subject to the terms of this
                    Agreement, Isis hereby grants to Roche:</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z3b20e260e1dc499883cb39db12de9627">

            <tr>
              <td style="width: 108pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(i)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>a worldwide, exclusive, sublicensable license under any Brain Shuttle-Specific Collaboration Patents, Linker-Specific Collaboration Patents and Omnibus Collaboration Patents solely or jointly-owned by Isis or its Affiliates, to
                  research, develop, manufacture, have manufactured and commercialize products comprising an active pharmaceutical ingredient and the Brain Shuttle Technology (each such product, a &#8220;<font style="font-weight: bold; font-style: italic;">BS-Specific


                    Drug</font>&#8221;); and</div>
              </td>
            </tr>

        </table>
        <div>&#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="zb19011d4496e45ed810bef34ab5e0e71">

            <tr>
              <td style="width: 108pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(ii)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>a worldwide, non-exclusive, sublicensable license under any Linker-Specific Collaboration Patents and Omnibus Collaboration Patents solely or jointly-owned by Isis or its Affiliates, to research, develop, manufacture, have manufactured
                  and commercialize products.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z3b5f4f1f24ff437182edc654013105e2">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Licenses to Isis to Brain Shuttle Collaboration Patents</u></font><font style="font-size: 10pt;">. Subject to the terms of this Agreement
                    (including Isis&#8217; exclusivity covenants under <u>Section 2.1.1</u>), Roche hereby grants to Isis:</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z6cc2912ca172468a8561b3447c276e1d">

            <tr>
              <td style="width: 108pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(i)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>a worldwide, exclusive, sublicensable license under any ASO-Specific Collaboration Patents, Linker-Specific Collaboration Patents and Omnibus Collaboration Patents solely or jointly-owned by Roche or its Affiliates, to research,
                  develop, manufacture, have manufactured and commercialize products that include an ASO as an active pharmaceutical ingredient and are not BS-Specific Drugs; and</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">16</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z34a219f89c3843a49113ff99acfb0225">

            <tr>
              <td style="width: 108pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(ii)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>a worldwide, non-exclusive, sublicensable license under any Linker-Specific Collaboration Patents and Omnibus Collaboration Patents solely or jointly-owned by Roche or its Affiliates, to research, develop, manufacture, have
                  manufactured and commercialize products.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z3fd9655cb801463ea8fb6c2bccb17cdf">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">4.1.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Amendment to the Existing Diagnostic Agreement</u></font><font style="font-size: 10pt;">. After Option exercise, Isis and Roche will execute an amendment to
                    the Existing Diagnostic Agreement on terms mutually agreed by Roche and Isis, which amendment will include granting Roche a non-exclusive, sublicensable, worldwide license, with the right to sublicense (through multiple tiers) under
                    Patent Rights and/or Know-How Controlled by Isis necessary or useful to develop and commercialize HTT diagnostic products (including diagnostic products and/or services to select patients who will use Products).</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z58fe0fd662d04fc9884a78c9c4fc050e">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">4.1.4.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Sublicense Rights</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z4edbc65fbce34656ad2644d4c6f2405d">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Subject to the terms of this Agreement, Roche will have the right to grant sublicenses under any license granted under <u>Section </u>4.1.1 above:</div>
              </td>
            </tr>

        </table>
        <div>&#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="z75b5b127eb0f4cb6b02d1aff1a1c6d17">

            <tr>
              <td style="width: 108pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(i)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>under the Isis Core Technology Patents, Isis Product-Specific Patents and Isis Know-How to an Affiliate of Roche or a Third Party; and</div>
              </td>
            </tr>

        </table>
        <div>&#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="ze5519c6a180f4553bc336aa3057d6047">

            <tr>
              <td style="width: 108pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(ii)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>under the Isis Manufacturing and Analytical Patents and Isis Manufacturing and Analytical Know-How solely to (y) an Affiliate of Roche or (z) [<font style="color: rgb(0, 0, 0);">***</font>] (each, a &#8220;<font style="font-weight: bold; font-style: italic;">Licensed CMO</font>&#8221;).</div>
              </td>
            </tr>

        </table>
        <div>&#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="z13c7810455a141a1935a044e4fa8517d">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Requests to Grant Sublicenses to CMOs</u></font><font style="font-size: 10pt;">. If Roche provides Isis with a written request that Isis grant a license
                    under the Isis Manufacturing and Analytical Patents and Isis Manufacturing and Analytical Know-How to a CMO designated by Roche that is not a Licensed CMO, solely for such CMO to manufacture Products for Roche, its Affiliate or
                    Sublicensee in a manufacturing facility owned or operated by such CMO, [<font style="color: rgb(0, 0, 0);">***</font>].</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z056059a0088446debdb1245aacd3ee1a">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(c)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Enforcing Sublicenses</u></font><font style="font-size: 10pt;">. Each sublicense by Roche under this Agreement will be subject to, and consistent with, the
                    terms of this Agreement.&#160; Roche shall be responsible to ensure compliance by its Sublicensees with the terms and conditions of this Agreement. If Isis reasonably believes a Roche Sublicensee may be violating the terms of this Agreement,
                    then, within 30 days after Isis delivers a written request to Roche, Roche will provide Isis a full and complete copy of the sublicense Roche entered with such Sublicensee.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">17</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="zc97b976944064e3ebc7b1b74698df3ec">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(d)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Effect of Termination on Sublicenses</u></font><font style="font-size: 10pt;">. If this Agreement terminates for any reason, any Sublicensee granted a
                    sublicense by Roche to Develop or Commercialize Products will, from the effective date of such termination, automatically become a direct licensee of Isis with respect to the rights sublicensed to the Sublicensee by Roche; <font style="font-style: italic;">so long as</font> (i) such Sublicensee is not in breach of its sublicense agreement, (ii) such Sublicensee agrees in writing to comply with all of the terms of this Agreement to the extent applicable to the
                    rights originally sublicensed to it by Roche, and (iii) such Sublicensee agrees to pay directly to Isis such Sublicensee&#8217;s payments under this Agreement to the extent applicable to the rights sublicensed to it by Roche. Roche agrees
                    that it will confirm clause (i) of the foregoing in writing at the request and for the benefit of Isis and if requested, the Sublicensee.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zd572224e0fc441589f1967332ab35c59">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">4.1.5.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>No Implied Licenses</u></font><font style="font-size: 10pt;">. All rights in and to Licensed Technology not expressly licensed to Roche under this Agreement
                    are hereby retained by Isis or its Affiliates. All rights in and to Roche Technology not expressly licensed or assigned to Isis under this Agreement, are hereby retained by Roche or its Affiliates. Except as expressly provided in this
                    Agreement, no Party will be deemed by estoppel or implication to have granted the other Party any license or other right with respect to any intellectual property.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z7e9cb00dc68849debd27dc7da6e92276">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">4.1.6.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>License Conditions; Limitations</u></font><font style="font-size: 10pt;">. Subject to <u>Section 6.11</u>, any license granted under <u>Section 4.1.1</u>
                    and the sublicense rights under <u>Section 4.1.4</u> are subject to and limited by (i) the Permitted Licenses, (ii) the Prior Agreements, and (iii) the Isis In-License Agreements, in each case to the extent the provisions of such
                    obligations or agreements are specifically disclosed to Roche in writing (or via electronic data room).</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zaf2d7642437541e4aac9f6b963082f1f">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">4.1.7.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Trademarks for Products</u></font><font style="font-size: 10pt;">. After Option exercise, Roche is solely responsible for all trademarks, trade dress, logos,
                    slogans, designs, copyrights and domain names used on or in connection with Products licensed under <u>Section 4.1.1</u>.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z84b91c9e3da5421ca7110518f170dc5e">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">4.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Technology Transfer after Option Exercise</u></font><font style="font-size: 10pt;">. After Option exercise pursuant to a technology transfer plan to be
                    mutually agreed by Isis and Roche, and subject to <u>Section 4.2.3</u>, Isis will:</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z7b9ea1964fe149348f78e13c0abdf815">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">4.2.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Licensed Know-How &#8211; Generally</u></font><font style="font-size: 10pt;">. Deliver to Roche copies of Licensed Know-How (other than the Isis Manufacturing and
                    Analytical Know-How) in the Field in Isis&#8217; possession not previously provided hereunder, for use solely in accordance with the license granted under <u>Section 4.1.1</u> to Roche together with all regulatory documentation (including
                    drafts) related to Products. To assist with the transfer of such Licensed Know-How, Isis will make its personnel reasonably available to Roche during normal business hours to transfer such Licensed Know-How under this <u>Section 4.2.1</u>.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">18</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z3aaef92a2f8f4de38f13f028a50f2168">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">4.2.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Isis Manufacturing and Analytical Know-How</u></font><font style="font-size: 10pt;">. Deliver, at Roche&#8217;s election, to one of either (i) Roche, or (ii) a
                    Licensed CMO solely to Manufacture API on Roche&#8217;s behalf, copies of the Isis Manufacturing and Analytical Know-How relating to Products in Isis&#8217; possession not previously provided hereunder, which is necessary for the exercise by Roche,
                    its Affiliates or a Third Party of the Manufacturing rights granted under <u>Section 4.1.1</u>.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z34f1afbafa0e4d29a74b3d11d5387400">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">4.2.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Technology Transfer Costs</u></font><font style="font-size: 10pt;">. Isis will perform the technology transfer activities under this <u>Section 4.2</u> for
                    up to [<font style="color: rgb(0, 0, 0);">***</font>] FTE hours (free of charge to Roche) of Isis&#8217; time. Thereafter, if requested by Roche, Isis will provide Roche with a reasonable level of assistance in connection with such transfer,
                    which Roche will reimburse Isis for Isis&#8217; time incurred in providing such assistance at Isis&#8217; FTE rate, and any of Isis&#8217; reasonable travel expenses for travel requested by Roche, and any outside consultants&#8217; costs and consultants&#8217;
                    reasonable travel expenses incurred by Isis agreed in advance by Roche.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="text-align: center; font-weight: bold;">&#160;ARTICLE 5.</div>
        <div style="text-align: center; font-weight: bold;">DEVELOPMENT, MANUFACTURING AND COMMERCIALIZATION</div>
        <div>&#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="ze676b6ad125d402e8d0b7359a9455662">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">5.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Roche Diligence</u></font><font style="font-size: 10pt;">. After Option exercise, subject to the terms of this Agreement, Roche is solely responsible for all
                    Development, Manufacturing and Commercialization activities, and for all costs and expenses associated therewith, with respect to the Development, Manufacture and Commercialization of Products. Roche will use Commercially Reasonable
                    Efforts to Develop, Manufacture and Commercialize Products, including to meet the timelines and milestones set forth in the Isis Development Candidate-R&amp;D Plan, the IDCP and the Specific Performance Milestone Events.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="text-align: justify; margin-left: 36pt;">Prior to Initiation of the first Registration-Directed Trial for a given Product, Roche will prepare a Development and global integrated development and commercialization plan (&#8220;<font style="font-weight: bold; font-style: italic;">IDCP</font>&#8221;) outlining key aspects for Developing such Product through Approval, and Roche&#8217;s worldwide strategy to launch and Commercialize such Product. The IDCP will incorporate and replace the
          applicable R&amp;D Plan and will take the form of, and contain information consistent with, Roche&#8217;s Development and Commercialization plans for its similar products at similar stages of development or commercialization, including Product Sales
          forecasts. Once Roche has prepared such plan, Roche will update the IDCP consistent with Roche&#8217;s standard practice and provide such updates to Isis at least Annually.</div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">19</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z1d625e3164a840d4afbd703b013c011b">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">5.1.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Independent Expert</u></font><font style="font-size: 10pt;">. After Option exercise, Roche will have the final decision-making authority regarding which
                    Product to [<font style="color: rgb(0, 0, 0);">***</font>], and Roche will present its decision to the JSC. If Roche decides to progress the [<font style="color: rgb(0, 0, 0);">***</font>], and the JSC does not unanimously agree with
                    Roche&#8217;s decision to do so, the JSC will appoint a single, independent Third Party expert (&#8220;<font style="font-weight: bold; font-style: italic;">Independent Expert</font>&#8221;) mutually agreed upon by the Parties with appropriate expertise
                    and professional credentials to evaluate Roche&#8217;s decision. Each Party will have the opportunity to present its position to the Independent Expert. The Independent Expert, when considering its recommendation, will consider such factors
                    as [<font style="color: rgb(0, 0, 0);">***</font>], available clinical and pre-clinical data for [<font style="color: rgb(0, 0, 0);">***</font>], the commercial potential of the Development Candidates and the competitive environment.
                    The Independent Expert will make his or her own recommendation to the JSC regarding whether the Brain Shuttle Development Candidate or the Isis Development Candidate should [<font style="color: rgb(0, 0, 0);">***</font>]. Roche will not
                    be required to adopt the Independent Expert&#8217;s recommendation. If the Independent Expert recommends that the [<font style="color: rgb(0, 0, 0);">***</font>], then Roche will pay Isis the royalty rate under <font style="font-variant: small-caps;"><u>Table</u></font><u> 4</u> of<u> Section 6.7.1</u> applicable to [<font style="color: rgb(0, 0, 0);">***</font>]. If the Independent Expert recommends that the [<font style="color: rgb(0, 0, 0);">***</font>], Roche will
                    pay the costs of the Independent Expert.&#160; If the Independent Expert recommends that the [<font style="color: rgb(0, 0, 0);">***</font>], Roche and Isis will each pay 50% of the costs of the Independent Expert.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z8b2988811c4046e3a363fbd335323dc9">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">5.1.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Phase 2 Trials</u></font><font style="font-size: 10pt;">. The Phase 2 Trial for the first Isis Development Candidate will be designed in accordance with the
                    Phase 2 Trial design set forth in the Isis Development Candidate-R&amp;D Plan, taking into consideration the results of the Phase 1 Trial. The Phase 2 Trials for all other Development Candidates will be designed in accordance with the
                    applicable R&amp;D Plan. Roche will keep Isis informed of the progress and status of each Phase 2 Trial. Roche will notify Isis in writing promptly after Roche completes a Phase 2 Trial under the applicable R&amp;D Plan. Promptly after
                    such notice, once the data generated under the statistical analysis plan for a Phase 2 Trial is available to Roche, Roche will provide such data to Isis.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z3634c34d140b452ca0619b9243054dea">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">5.1.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Registration-Directed Trials</u></font><font style="font-size: 10pt;">. The Registration-Directed Trials will be designed in accordance with the
                    Registration-Directed Trial designs set forth in the applicable IDCP. Roche will keep Isis informed of the progress and status of each Registration-Directed Trial. Roche will notify Isis in writing promptly after Roche completes each
                    Registration-Directed Trial under the applicable IDCP. Promptly after such notice, once the data generated under the statistical analysis plan for a Registration-Directed Trial is available to Roche, Roche will provide such data to
                    Isis.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zb57053c284454af1960fa7eab5ee3784">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">5.1.4.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Investigator&#8217;s Brochure</u></font><font style="font-size: 10pt;">. After Option Exercise, in addition to the IDCP, Roche will keep Isis reasonably informed
                    with respect to the status, activities and progress of Development of Products by providing updated versions of the Investigator&#8217;s Brochure to Isis Annually and upon any substantive change to the safety or risk of the Products.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z04894904c77643c98ad115462b21d533">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">5.1.5.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Participation in Regulatory Meetings</u></font><font style="font-size: 10pt;">. Each Party will provide the other Party with as much advance written notice
                    as practicable of any meetings such Party has or plans to have with a Regulatory Authority regarding pre-approval or Approval matters for a Product, and will allow the other Party (at such other Party&#8217;s own expense) to participate in
                    any such meetings as an observer.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">20</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="zb2cf5e9b714e4ef78b825b0aa54a03fa">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">5.1.6.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Regulatory Communications</u></font><font style="font-size: 10pt;">. Each Party will provide the other Party with copies of documents and communications
                    submitted to and received from Regulatory Authorities that materially impact the Development or Commercialization of Products for the other Party&#8217;s review and comment, and the submitting Party will consider in good faith including any
                    comments provided by the reviewing Party to such documents and communications.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zf7c9edf330ae4d2da97e3287cdd2f33b">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">5.1.7.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Participation in Roche Clinical Development Team Meetings</u></font><font style="font-size: 10pt;">. [<font style="color: rgb(0, 0, 0);">***</font>], Roche
                    will permit Isis to participate in Roche&#8217;s key clinical development team meetings for Products (i.e., meetings that are likely to have a material impact on the Development of the Product(s)) (each such meeting, a &#8220;<font style="font-weight: bold; font-style: italic;">Key Meeting</font>&#8221;), at Isis&#8217; reasonable request. Isis&#8217; and Roche&#8217;s respective designated clinical leaders will work together to come up with a schedule of such Key Meetings, giving Isis
                    as much advance written notice as practicable so that Isis may, at Isis&#8217; expense, plan for its participation in such meetings.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="ze09a083dd2ca4e9598fd7b4722f9bcf9">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">5.1.8.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Class Generic Claims</u></font><font style="font-size: 10pt;">. If Roche intends to make any claims in a Product label or regulatory filing that are class
                    generic to ASOs or Isis&#8217; chemistry platform(s), Roche will provide such claims and regulatory filings to Isis in advance and will consider in good faith any proposals and comments made by Isis.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="za1b3edde303f4097a36f36b9f1845d30">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">5.1.9.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Applicable Laws</u></font><font style="font-size: 10pt;">. Roche will perform its activities pursuant to this Agreement in compliance with applicable good
                    laboratory and clinical practices and cGMP.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z6b34f1a1ec3e46f1b06e5a088e238303">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">5.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt; font-weight: bold;"><font style="font-size: 10pt;"><u>IND; Global Safety Database</u>.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zb85dfdf20f77479daea15a428c93b69b">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">5.2.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>IND</u></font><font style="font-size: 10pt;">. The Parties acknowledge that until the first Development Candidate completes a Phase 1 Trial, Isis will be the
                    holder of the IND for such Development Candidate. After Option exercise, upon transfer of Isis&#8217; Development Candidate IND to Roche and assumption by Roche of regulatory responsibilities under the IND, Roche will assume responsibility
                    for the global safety database related to such Development Candidate. After Option exercise, Roche will be solely responsible for reporting to Regulatory Authorities in accordance with the Applicable Law for expeditable adverse events
                    and for periodic safety reporting relating to the safety of such Development Candidate and all subsequent Development Candidates and will furnish copies of such reports to Isis.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">21</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="zd866d4e199ad4c93ade4e7f210dce05d">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">5.2.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Isis&#8217; Antisense Safety Database</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z0541d9ddc2fa4993b18f8297fff8c71c">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Isis 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;">Isis Internal ASO Safety Database</font>&#8221;). In an effort to maximize understanding of the safety profile and pharmacokinetics of Isis compounds, after Option exercise, Roche will cooperate
                  in connection with populating the Isis Internal ASO Safety Database. To the extent collected by Roche and in the form in which Roche uses/stores such information for its own purposes, Roche will make available to Isis information
                  concerning toxicology, pharmacokinetics, safety pharmacology study(ies), serious adverse events and other safety information related to Products as soon as practicable following the date such information is available to Roche (but Roche
                  will make such information available to Isis starting no later than thirty (30) days after Roche&#8217;s receipt of such information). In connection with any reported serious adverse event, Roche will provide Isis all serious adverse event
                  reports, including initial, interim, follow-up, amended, and final reports. In addition, with respect to Products, Roche will make available to Isis copies of Annual safety updates filed with each IND and the safety sections of any final
                  Clinical Study reports within thirty (30) days following the date such information is filed or is available to Roche, as applicable. Furthermore, Roche will promptly make available to Isis any supporting data and answer any follow-up
                  questions reasonably requested by Isis. All such information disclosed by Roche to Isis will be Roche Confidential Information; <font style="font-style: italic;">provided, however</font>, that Isis may disclose any such Roche
                  Confidential Information to (i) Isis&#8217; other partners pursuant to <u>Section 5.2.2(b)</u> below if such information is regarding class generic properties of ASOs, or (ii) any Third Party, in each case, so long as Isis does not disclose
                  the identity of a Product or Roche. Roche will contact Isis&#8217; Chief Medical Officer at Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, California 92010 (or at such other address/contact designated in writing by Isis) for matters
                  related to the Isis Internal ASO Safety Database. Roche will also cause its Affiliates and Sublicensees to comply with this <u>Section 5.2.2(a)</u>.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z9a74df89f14c44c08ece3a11f193beaa">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Isis utilizes the information in the Isis Internal ASO Safety Database to conduct analyses to keep Isis and its partners informed regarding class generic properties of ASOs, including with respect to safety. As such, if and when Isis
                  identifies safety or other related issues that may be relevant to a Product (including any potential class-related toxicity), Isis will promptly inform Roche of such issues and, if requested, provide the data supporting Isis&#8217; conclusions.</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="text-align: center; font-weight: bold;">ARTICLE 6.</div>
        <div style="text-align: center; font-weight: bold;">FINANCIAL PROVISIONS</div>
        <div>&#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="z4a7fcc74aa9d4ef1866ec9b3343517de">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Option Fee</u></font><font style="font-size: 10pt;">. In partial consideration for Roche&#8217;s Option hereunder, within ten (10) days following the Effective
                    Date and receipt by Roche of an invoice from Isis, Roche will pay Isis an Option fee equal to thirty million dollars (US$30,000,000).</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z82e32b26e3404f3f94af1823358a3620">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Milestone Payments for Achievement of Pre-Licensing Milestone Events</u></font><font style="font-size: 10pt;">. As further consideration for Roche&#8217;s Option,
                    Roche will pay to Isis the milestone payments as set forth in <font style="font-variant: small-caps;"><u>Table 1</u></font> below when a milestone event (each, a &#8220;<font style="font-weight: bold; font-style: italic;">Pre-Licensing</font><font style="font-style: italic;">&#160;</font><font style="font-weight: bold; font-style: italic;">Milestone Event</font><font style="font-style: italic;">&#8221;</font>) listed in <font style="font-variant: small-caps;"><u>Table 1</u>&#160;</font>is
                    first achieved by the applicable Development Candidate:</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">22</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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%; border-collapse: collapse; text-align: left; color: rgb(0, 0, 0);" id="zfda0260211d64306b61c740e2613f85a">

            <tr>
              <td colspan="4" style="width: 100%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
                <div style="text-align: center; font-variant: small-caps; font-weight: bold;"><u>Table 1</u></div>
              </td>
            </tr>
            <tr>
              <td style="width: 23.68%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                <div>&#160;</div>
                <div style="font-weight: bold;">Pre-Licensing </div>
                <div style="font-weight: bold;">Milestone Events</div>
                <div>&#160;</div>
              </td>
              <td style="width: 25.38%; vertical-align: middle; border-left: 2px solid rgb(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;"><u>Column 1</u></div>
                <div style="text-align: center; font-weight: bold;">Milestone Payments </div>
                <div style="text-align: center; font-weight: bold;">for the Isis </div>
                <div style="text-align: center; font-weight: bold;">Development</div>
                <div style="text-align: center; font-weight: bold;"> Candidate to First </div>
                <div style="text-align: center; font-weight: bold;">Achieve Milestone</div>
                <div style="text-align: center; font-weight: bold;"> Event</div>
              </td>
              <td style="width: 26.32%; 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; font-weight: bold;"><u>Column 2</u></div>
                <div style="text-align: center; font-weight: bold;">Milestone Payments <br>
                </div>
                <div style="text-align: center; font-weight: bold;">for Additional Isis </div>
                <div style="text-align: center; font-weight: bold;">Development </div>
                <div style="text-align: center; font-weight: bold;">Candidate to Achieve </div>
                <div style="text-align: center; font-weight: bold;">Milestone Event</div>
              </td>
              <td style="width: 24.62%; vertical-align: top; border-left: 2px solid rgb(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;"><u>Column 3</u></div>
                <div style="text-align: center; font-weight: bold;">Milestone Payments </div>
                <div style="text-align: center; font-weight: bold;">for First Brain </div>
                <div style="text-align: center; font-weight: bold;">Shuttle Development </div>
                <div style="text-align: center; font-weight: bold;">Candidate to Achieve Milestone</div>
                <div style="text-align: center; font-weight: bold;"> Event</div>
              </td>
            </tr>
            <tr>
              <td style="width: 23.68%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                <div>[<font style="color: rgb(0, 0, 0);">***</font>]</div>
              </td>
              <td style="width: 25.38%; vertical-align: middle; border-left: 2px solid rgb(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-size: 12pt;"><font style="font-size: 10pt;">[</font><font style="font-size: 10pt; color: rgb(0, 0, 0);">***</font><font style="font-size: 10pt;">]</font></div>
              </td>
              <td style="width: 26.32%; vertical-align: middle; border-left: 2px solid rgb(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>
              <td style="width: 24.62%; vertical-align: middle; border-left: 2px solid rgb(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-size: 12pt;"><font style="font-size: 10pt;">[</font><font style="font-size: 10pt; color: rgb(0, 0, 0);">***</font><font style="font-size: 10pt;">]</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 23.68%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                <div>[<font style="color: rgb(0, 0, 0);">***</font>]</div>
              </td>
              <td style="width: 25.38%; vertical-align: middle; border-left: 2px solid rgb(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-size: 12pt;"><font style="font-size: 10pt;">[</font><font style="font-size: 10pt; color: rgb(0, 0, 0);">***</font><font style="font-size: 10pt;">]</font></div>
              </td>
              <td style="width: 26.32%; vertical-align: middle; border-left: 2px solid rgb(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-size: 12pt;"><font style="font-size: 10pt;">[</font><font style="font-size: 10pt; color: rgb(0, 0, 0);">***</font><font style="font-size: 10pt;">]</font></div>
              </td>
              <td style="width: 24.62%; vertical-align: middle; border-left: 2px solid rgb(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><sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">&#8224;</sup>]</div>
              </td>
            </tr>

        </table>
        <div><br>
        </div>
        <div style="text-align: justify; margin-left: 36pt;">*[<font style="color: rgb(0, 0, 0);">***</font>] milestone payment is only payable once in accordance with <u>Section 1.8.1(b).</u></div>
        <div><br>
        </div>
        <div style="text-align: justify; margin-left: 36pt;"><sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">&#8224;</sup>This milestone payment is not payable by Roche if Roche has already paid Isis the [<font style="color: rgb(0, 0, 0);">***</font>] milestone payment under <u>Column 1</u> of this <font style="font-variant: small-caps;"><u>Table 1</u></font>.</div>
        <div style="text-align: justify;"> <br>
        </div>
        <div style="text-align: justify; margin-left: 36pt;">Except for the [<font style="color: rgb(0, 0, 0);">***</font>] milestone payment in <u>Column 2</u> of <font style="font-variant: small-caps;"><u>Table</u></font><u> 1</u> for an Additional
          Isis Development Candidate, Roche will pay to Isis the Milestone Event payments as set forth in <font style="font-variant: small-caps;"><u>Table 1</u></font> after the applicable Milestone Event is first achieved by a Development Candidate even
          if Roche has exercised the Option prior to achievement of the Milestone Event.</div>
        <div>&#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="z93da812a8b854ed0b9f6021092b11c0f">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>License Fee</u></font><font style="font-size: 10pt;">. Pursuant to <u>Section 3.2</u>, subsequent to Roche&#8217;s written notice to exercise its Option in
                    accordance with this Agreement, Roche will pay to Isis a license fee of [<font style="color: rgb(0, 0, 0);">***</font>] within thirty (30) days after providing such written notice and receipt by Roche of an invoice from Isis.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z2e4cf67823964012a5fcde5e4b62ef36">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.4.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Milestone Payments for Achievement of Post-Licensing Milestone Events</u></font><font style="font-size: 10pt;">. Roche will pay Isis the milestone payments
                    set forth in <font style="font-variant: small-caps;"><u>Table 2</u></font> below when a milestone event (each, a <font style="font-style: italic;">&#8220;</font><font style="font-weight: bold; font-style: italic;">Post-Licensing</font><font style="font-style: italic;">&#160;</font><font style="font-weight: bold; font-style: italic;">Milestone Event</font><font style="font-style: italic;">&#8221;</font>) listed in <font style="font-variant: small-caps;"><u>Table 2</u></font> is
                    first achieved by a Product:</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">23</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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%; border-collapse: collapse; text-align: left; color: rgb(0, 0, 0);" id="ze4d2ab86ab0c43758dd176da5c865ce2">

            <tr>
              <td colspan="3" style="width: 100%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
                <div style="text-align: center; font-variant: small-caps; font-weight: bold;"><u>Table 2</u></div>
              </td>
            </tr>
            <tr>
              <td style="width: 34.2%; vertical-align: middle; border-left: 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;">Post-Licensing Milestone</div>
                <div style="font-weight: bold;"> Event</div>
              </td>
              <td style="width: 34.98%; vertical-align: middle; border-left: 2px solid rgb(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;"><u>Column 1</u></div>
                <div style="text-align: center; font-weight: bold;">Milestone Payment for First </div>
                <div style="text-align: center; font-weight: bold;">Product to Achieve Milestone</div>
                <div style="text-align: center; font-weight: bold;"> Event</div>
              </td>
              <td style="width: 30.82%; vertical-align: top; border-left: 2px solid rgb(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;"><u>Column 2</u></div>
                <div style="text-align: center; font-weight: bold;">Milestone Payment for</div>
                <div style="text-align: center; font-weight: bold;"> Each Product After the</div>
                <div style="text-align: center; font-weight: bold;"> First Product to Achieve Milestone </div>
                <div style="text-align: center; font-weight: bold;">Event</div>
              </td>
            </tr>
            <tr>
              <td style="width: 34.2%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                <div>[<font style="color: rgb(0, 0, 0);">***</font>]</div>
              </td>
              <td style="width: 34.98%; vertical-align: middle; border-left: 2px solid rgb(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>
              <td style="width: 30.82%; vertical-align: top; border-left: 2px solid rgb(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: 34.2%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                <div>[<font style="color: rgb(0, 0, 0);">***</font>]</div>
              </td>
              <td style="width: 34.98%; vertical-align: middle; border-left: 2px solid rgb(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>
              <td style="width: 30.82%; vertical-align: top; border-left: 2px solid rgb(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: 34.2%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                <div>[<font style="color: rgb(0, 0, 0);">***</font>]</div>
              </td>
              <td style="width: 34.98%; vertical-align: middle; border-left: 2px solid rgb(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>
              <td style="width: 30.82%; vertical-align: top; border-left: 2px solid rgb(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: 34.2%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                <div>[<font style="color: rgb(0, 0, 0);">***</font>]</div>
              </td>
              <td style="width: 34.98%; vertical-align: middle; border-left: 2px solid rgb(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>
              <td style="width: 30.82%; vertical-align: top; border-left: 2px solid rgb(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: 34.2%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                <div>[<font style="color: rgb(0, 0, 0);">***</font>]</div>
              </td>
              <td style="width: 34.98%; vertical-align: middle; border-left: 2px solid rgb(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>
              <td style="width: 30.82%; vertical-align: top; border-left: 2px solid rgb(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: 34.2%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                <div>[<font style="color: rgb(0, 0, 0);">***</font>]</div>
              </td>
              <td style="width: 34.98%; vertical-align: middle; border-left: 2px solid rgb(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>
              <td style="width: 30.82%; vertical-align: top; border-left: 2px solid rgb(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: 34.2%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                <div>[<font style="color: rgb(0, 0, 0);">***</font>]</div>
              </td>
              <td style="width: 34.98%; vertical-align: middle; border-left: 2px solid rgb(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>
              <td style="width: 30.82%; vertical-align: top; border-left: 2px solid rgb(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="font-weight: bold; color: rgb(0, 0, 0);">***</font>]</div>
              </td>
            </tr>
            <tr>
              <td style="width: 34.2%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                <div>[<font style="color: rgb(0, 0, 0);">***</font>]</div>
              </td>
              <td style="width: 34.98%; vertical-align: middle; border-left: 2px solid rgb(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>
              <td style="width: 30.82%; vertical-align: top; border-left: 2px solid rgb(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: 34.2%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                <div>[<font style="color: rgb(0, 0, 0);">***</font>]</div>
              </td>
              <td style="width: 34.98%; vertical-align: middle; border-left: 2px solid rgb(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>
              <td style="width: 30.82%; vertical-align: top; border-left: 2px solid rgb(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>&#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="z9e2514fadeda40049d90df41c9e95f4f">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.5.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Milestone Payments for First Achievement of Sales Milestone Event</u></font><font style="font-size: 10pt;">. Roche will pay Isis the applicable one-time
                    milestone payments set forth in <font style="font-variant: small-caps;"><u>Table</u></font><u> 3</u> below after the first achievement of the listed events, by or on behalf of Roche or its Affiliates or Sublicensees. For clarity,
                    notwithstanding any provision to the contrary in this Agreement, any consideration received by Roche or its Affiliates from a Compulsory Sublicensee for the sale of Products in a given Calendar Year will be added to Net Sales of
                    Products for such year for purposes of determining whether any of the Sales Milestones in <font style="font-variant: small-caps;"><u>Table</u></font><u> 3</u> have been achieved.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <table cellspacing="0" cellpadding="0" border="0" align="center" style="border-collapse: collapse; width: 60%; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; text-align: left;" id="z014109b6f5c148c3a5f4efe75925d919">

            <tr>
              <td colspan="2" style="border-bottom: 2px solid #000000; border-left: 2px solid #000000; border-right: 2px solid #000000; border-top: 2px solid #000000; vertical-align: middle;">
                <div style="text-align: center; font-variant: small-caps; font-weight: bold;"><u>Table 3</u></div>
              </td>
            </tr>
            <tr>
              <td style="width: 30%; vertical-align: middle; border-left: 2px solid rgb(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;">Sales Milestone</div>
                <div>&#160;</div>
              </td>
              <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; font-weight: bold;">Sales Milestone</div>
                <div style="text-align: center; font-weight: bold;">Payment</div>
              </td>
            </tr>
            <tr>
              <td style="width: 30%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                <div>[<font style="color: rgb(0, 0, 0);">***</font>] in aggregate worldwide Annual Net Sales </div>
                <div>of Products comprising an Isis Development Candidate</div>
                <div>&#160;</div>
              </td>
              <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>&#160;</div>
                <div style="text-align: center;">[<font style="font-weight: bold; color: rgb(0, 0, 0);">***</font>]</div>
              </td>
            </tr>
            <tr>
              <td style="width: 30%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                <div>[<font style="color: rgb(0, 0, 0);">***</font>] in aggregate worldwide Annual Net Sales </div>
                <div>of Products comprising an Isis Development Candidate</div>
                <div>&#160;</div>
              </td>
              <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>&#160;</div>
                <div style="text-align: center;">[<font style="color: rgb(0, 0, 0);">***</font>]</div>
              </td>
            </tr>
            <tr>
              <td style="width: 30%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                <div>[<font style="color: rgb(0, 0, 0);">***</font>] in aggregate worldwide Annual Net Sales </div>
                <div>of Products comprising a Brain Shuttle</div>
                <div> Development Candidate</div>
                <div>&#160;</div>
              </td>
              <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>&#160;</div>
                <div style="text-align: center;">[<font style="color: rgb(0, 0, 0);">***</font>]</div>
              </td>
            </tr>
            <tr>
              <td style="width: 30%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                <div>[<font style="color: rgb(0, 0, 0);">***</font>] in aggregate worldwide Annual Net Sales of Products comprising a Brain Shuttle </div>
                <div>Development Candidate</div>
                <div>&#160;</div>
              </td>
              <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>&#160;</div>
                <div style="text-align: center;">[<font style="color: rgb(0, 0, 0);">***</font>]</div>
              </td>
            </tr>
            <tr>
              <td style="width: 30%; vertical-align: middle; border-left: 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 Sales Milestone Payments</div>
              </td>
              <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>&#160;</div>
                <div style="text-align: center;">[<font style="color: rgb(0, 0, 0);">***</font>]</div>
                <div>&#160;</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="text-align: justify; text-indent: -36pt; margin-left: 36pt; font-weight: bold;"></div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">24</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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" class="DSPFListTable" id="zdaca41e4a6204eba9d692c85fcd6f034" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

              <tr style="vertical-align: top;">
                <td style="vertical-align: top; width: 36pt;"><font style="font-weight: bold;">6.6.</font><br>
                </td>
                <td style="vertical-align: top;">
                  <div style="text-align: justify; font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u><font style="font-weight: bold;"><u>Limitations</u></font> on Milestone Payments; Exceptions; Notice</u></font><font style="font-size: 10pt;">.</font></div>
                </td>
              </tr>

          </table>
        </div>
        <div>&#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="z3f46825a19424225be56da9254d59a2e">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.6.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Each milestone payment set forth in <font style="font-variant: small-caps;"><u>Table 1</u>,</font> and in <u>Column 1</u> of <font style="font-variant: small-caps;"><u>Table 2</u></font> above, will be paid only once upon the first
                  achievement of the Milestone Event regardless of how many times such Milestone Event is achieved. On a Product-by-Product basis, each milestone payment set forth in <u>Column 2</u> of <font style="font-variant: small-caps;"><u>Table 2</u></font>
                  above will be paid only once upon the first achievement of the Milestone Event by the applicable Product. Each milestone payment set forth in <font style="font-variant: small-caps;"><u>Table 3</u></font> above will be paid only once upon
                  the first achievement of the Milestone Event.</div>
              </td>
            </tr>

        </table>
        <div>&#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="ze68b472089424e82bbd5c31f1b99d7f0">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.6.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>If a particular Milestone Event is not achieved because Development activities transpired such that achievement of such earlier Milestone Event was unnecessary or did not otherwise occur, then upon achievement of a later Milestone
                  Event the Milestone Event payment applicable to such earlier Milestone Event will also be due. For example, if a Party proceeds directly to [<font style="color: rgb(0, 0, 0);">***</font>] without achieving the [<font style="color: rgb(0, 0, 0);">***</font>] then upon achieving the [<font style="color: rgb(0, 0, 0);">***</font>] Milestone Event, both the [<font style="color: rgb(0, 0, 0);">***</font>] and [<font style="color: rgb(0, 0, 0);">***</font>] Milestone Event
                  payments are due.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z59451c5fc14641abb17b93c20b6e093d">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.6.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Each time a Milestone Event is achieved under this <u>ARTICLE 6</u>, the Party that achieved such Milestone Event will send to the other Party a written notice thereof promptly (but no later than ten (10) Business Days)
                  following the date of achievement of such Milestone Event and such payment will be due within thirty (30) days of the date such Milestone Event was achieved and receipt of an invoice by Roche from Isis.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z507be97648fb4b268c6beef1cca39002">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.7.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Royalty Payments to Isis</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zf3cda3ebe27845ac9f636f505be480bd">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.7.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Roche Full Royalty</u></font><font style="font-size: 10pt;">. As partial consideration for the rights granted to Roche hereunder, subject to the provisions
                    of this <u>Section 6.7.1</u> and <u>Section 6.7.2</u>, Roche will pay to Isis royalties on Annual worldwide Net Sales of Products sold by Roche, its Affiliates or Sublicensees, on a country-by-country and Product-by-Product basis, in
                    each case in the amounts as follows in <font style="font-variant: small-caps;"><u>Table 4</u></font> below (the &#8220;<font style="font-weight: bold; font-style: italic;">Roche Full Royalty</font>&#8221;):</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">25</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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%; border-collapse: collapse; text-align: left; color: #000000;" id="z8b9abbfad2614606937c563440fb1ef6">

            <tr>
              <td colspan="5" style="border-bottom: 2px solid #000000; border-left: 2px solid #000000; border-right: 2px solid #000000; border-top: 2px solid #000000; vertical-align: top; width: 100%;">
                <div style="text-align: center; font-variant: small-caps; font-weight: bold;"><u>Table 4</u></div>
              </td>
            </tr>
            <tr>
              <td style="width: 12.47%; vertical-align: top; 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: 28.88%; vertical-align: middle; 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 colspan="3" style="width: 58.65%; vertical-align: middle; border-left: #000000 2px solid; border-right: #000000 2px solid; border-bottom: #000000 2px solid;">
                <div style="text-align: center; font-weight: bold;">Royalty</div>
                <div style="text-align: center; font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;">Rate for Products</font><font style="font-size: 10pt;">&#160;<font style="font-weight: bold;">Comprising:</font></font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 12.47%; vertical-align: top; border-left: #000000 2px solid; border-right: #000000 2px solid; border-bottom: #000000 2px solid;">
                <div>&#160;</div>
                <div style="text-align: center; font-weight: bold;">Royalty</div>
                <div style="text-align: center; font-weight: bold;">Tier</div>
              </td>
              <td style="width: 28.88%; vertical-align: middle; border-left: #000000 2px solid; border-right: #000000 2px solid; border-bottom: #000000 2px solid;">
                <div>&#160;</div>
                <div style="font-weight: bold;">Annual Worldwide Net Sales</div>
              </td>
              <td style="width: 19.52%; vertical-align: middle; border-left: 2px solid rgb(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;">Isis Development</div>
                <div style="text-align: center; font-weight: bold;"> Candidate</div>
              </td>
              <td style="width: 19.9%; 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; font-weight: bold;">Brain Shuttle</div>
                <div style="text-align: center; font-weight: bold;"> Development </div>
                <div style="text-align: center; font-weight: bold;">Candidate</div>
              </td>
              <td style="width: 19.23%; vertical-align: top; border-left: 2px solid rgb(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;">Roche-Selected </div>
                <div style="text-align: center; font-weight: bold;">Brain Shuttle</div>
                <div style="text-align: center; font-weight: bold;">Development Candidate</div>
              </td>
            </tr>
            <tr>
              <td style="width: 12.47%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                <div style="text-align: center;">1</div>
              </td>
              <td style="width: 28.88%; vertical-align: top; border-left: #000000 2px solid; border-right: #000000 2px solid; border-bottom: #000000 2px solid;">
                <div>For the portion of Annual Worldwide Net Sales&#160; &#160; &#160; &#160; &lt; $[<font style="color: rgb(0, 0, 0);">***</font>]</div>
                <div>&#160;</div>
              </td>
              <td style="width: 19.52%; vertical-align: top; border-left: #000000 2px solid; border-right: #000000 2px solid; border-bottom: #000000 2px solid;">
                <div>&#160;</div>
                <div style="text-align: center;">[<font style="color: rgb(0, 0, 0);">***</font>]%</div>
              </td>
              <td style="width: 19.9%; vertical-align: top; border-left: #000000 2px solid; border-right: #000000 2px solid; border-bottom: #000000 2px solid;">
                <div>&#160;</div>
                <div style="text-align: center;">[<font style="color: rgb(0, 0, 0);">***</font>]%</div>
              </td>
              <td style="width: 19.23%; vertical-align: top; border-left: #000000 2px solid; border-right: #000000 2px solid; border-bottom: #000000 2px solid;">
                <div>&#160;</div>
                <div style="text-align: center;">[<font style="color: rgb(0, 0, 0);">***</font>]%</div>
              </td>
            </tr>
            <tr>
              <td style="width: 12.47%; vertical-align: top; border-left: 2px solid rgb(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: 28.88%; vertical-align: top; border-left: #000000 2px solid; border-right: #000000 2px solid; border-bottom: #000000 2px solid;">
                <div>For the portion of Annual Worldwide Net Sales&#160; &#160; &#160; &#160; <u>&gt;</u> $[<font style="color: rgb(0, 0, 0);">***</font>]</div>
                <div>but &lt; $[<font style="color: rgb(0, 0, 0);">***</font>]</div>
                <div>&#160;</div>
              </td>
              <td style="width: 19.52%; vertical-align: top; border-left: #000000 2px solid; border-right: #000000 2px solid; border-bottom: #000000 2px solid;">
                <div>&#160;</div>
                <div style="text-align: center;">[<font style="color: rgb(0, 0, 0);">***</font>]%</div>
              </td>
              <td style="width: 19.9%; vertical-align: top; border-left: #000000 2px solid; border-right: #000000 2px solid; border-bottom: #000000 2px solid;">
                <div>&#160;</div>
                <div style="text-align: center;">[<font style="color: rgb(0, 0, 0);">***</font>]%</div>
              </td>
              <td style="width: 19.23%; vertical-align: top; border-left: #000000 2px solid; border-right: #000000 2px solid; border-bottom: #000000 2px solid;">
                <div>&#160;</div>
                <div style="text-align: center;">[<font style="color: rgb(0, 0, 0);">***</font>]%</div>
              </td>
            </tr>
            <tr>
              <td style="width: 12.47%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
                <div style="text-align: center;">3</div>
              </td>
              <td style="width: 28.88%; vertical-align: top; border-left: #000000 2px solid; border-right: #000000 2px solid; border-bottom: #000000 2px solid;">
                <div>For the portion of Annual Worldwide Net Sales&#160; &#160; &#160; &#160; <u>&gt;</u> $[<font style="color: rgb(0, 0, 0);">***</font>]</div>
                <div>&#160;but &lt; $[<font style="color: rgb(0, 0, 0);">***</font>]</div>
                <div>&#160;</div>
              </td>
              <td style="width: 19.52%; vertical-align: top; border-left: #000000 2px solid; border-right: #000000 2px solid; border-bottom: #000000 2px solid;">
                <div>&#160;</div>
                <div style="text-align: center;">[<font style="color: rgb(0, 0, 0);">***</font>]%</div>
              </td>
              <td style="width: 19.9%; vertical-align: top; border-left: #000000 2px solid; border-right: #000000 2px solid; border-bottom: #000000 2px solid;">
                <div>&#160;</div>
                <div style="text-align: center;">[<font style="color: rgb(0, 0, 0);">***</font>]%</div>
              </td>
              <td style="width: 19.23%; vertical-align: top; border-left: #000000 2px solid; border-right: #000000 2px solid; border-bottom: #000000 2px solid;">
                <div>&#160;</div>
                <div style="text-align: center;">[<font style="color: rgb(0, 0, 0);">***</font>]%</div>
              </td>
            </tr>
            <tr>
              <td style="width: 12.47%; vertical-align: top; border-left: 2px solid rgb(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: 28.88%; vertical-align: top; border-left: #000000 2px solid; border-right: #000000 2px solid; border-bottom: #000000 2px solid;">
                <div>For the portion of Annual Worldwide Net Sales&#160; &#160; &#160; &#160; <u>&gt;</u> $[<font style="color: rgb(0, 0, 0);">***</font>]</div>
                <div>&#160;</div>
              </td>
              <td style="width: 19.52%; vertical-align: top; border-left: #000000 2px solid; border-right: #000000 2px solid; border-bottom: #000000 2px solid;">
                <div>&#160;</div>
                <div style="text-align: center;">[<font style="color: rgb(0, 0, 0);">***</font>]%</div>
              </td>
              <td style="width: 19.9%; vertical-align: top; border-left: #000000 2px solid; border-right: #000000 2px solid; border-bottom: #000000 2px solid;">
                <div>&#160;</div>
                <div style="text-align: center;">[<font style="color: rgb(0, 0, 0);">***</font>]%</div>
              </td>
              <td style="width: 19.23%; vertical-align: top; border-left: #000000 2px solid; border-right: #000000 2px solid; border-bottom: #000000 2px solid;">
                <div>&#160;</div>
                <div style="text-align: center;">[<font style="color: rgb(0, 0, 0);">***</font>]%</div>
              </td>
            </tr>

        </table>
        <div>&#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="z45d2d034cd824910826aa0351130686f">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Annual worldwide Net Sales for a particular Product will be calculated by [<font style="color: rgb(0, 0, 0);">***</font>]. For clarity, notwithstanding any provision to the contrary in this Agreement, any consideration received by
                  Roche or its Affiliates from a Compulsory Sublicensee solely for the sale of Products in a given Calendar Year will be added to Net Sales of Products for such year for purposes of determining which royalty tier (and therefore which
                  royalty rate) applies to a particular Product in <font style="font-variant: small-caps;"><u>Table</u></font><u> 4</u>.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z5fc03035bdad466c911a0ee1e216b4ad">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Roche will pay Isis royalties on Net Sales of Products arising from named patient and other similar programs under Applicable Laws, and Roche will provide reports and payments to Isis consistent with <u>Section 6.12</u>. No royalties
                  are due on Net Sales of Products arising from compassionate use and other programs providing for the delivery of Product at no cost. The sales of Products arising from named patient, compassionate use or other similar programs will not be
                  considered a First Commercial Sale for purposes of determining the Full Royalty Period.<font style="color: rgb(0, 0, 0);">&#160;</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z94c2c6b1084a47ed909007d23be4e2bf">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.7.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Application of Royalty Rates</u></font><font style="font-size: 10pt;">. All royalties set forth under <u>Section 6.7.1</u> are subject to the provisions of
                    this <u>Section 6.7.2</u>, and are payable as follows:</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">26</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="za6f6ed7a2c0a4fd7889f313f94294488">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Full Royalty Period</u></font><font style="font-size: 10pt;">. Roche&#8217;s obligation to pay Isis the Roche Full Royalty above with respect to a Product will
                    continue on a country-by-country and Product-by-Product basis from the date of First Commercial Sale of such Product until the later of the date of expiration of (i) the last Valid Claim within the Licensed Patents or the Brain Shuttle
                    Collaboration Patents Covering such Product in the country in which such Product is used or sold, (ii) the data exclusivity period conferred by the applicable Regulatory Authority in such country with respect to such Product (<u>e.g.</u>,
                    such as in the case of an orphan drug), or (iii) the [<font style="color: rgb(0, 0, 0);">***</font>] anniversary of the First Commercial Sale of such Product in such country; <font style="font-style: italic;">provided, however</font>,
                    that, on a country-by-country and Product-by-Product basis, if neither of the periods set forth in clause (i) and clause (ii) of this <u>Section 6.7.2(a)</u> apply to a Product, then the Roche Full Royalty will continue to apply
                    through the [<font style="color: rgb(0, 0, 0);">***</font>] anniversary of the First Commercial Sale of such Product in such country <font style="font-style: italic;"><u>unless</u></font> a [<font style="color: rgb(0, 0, 0);">***</font>]
                    in such country, at which time in lieu of paying the Roche Full Royalty, Roche will pay Isis the Roche Reduced Royalty for such Product in such country in accordance with <u>Section 6.7.2(b)</u> (such royalty period, the &#8220;<font style="font-weight: bold; font-style: italic;">Full Royalty Period</font>&#8221;). For clarity, (X) Licensed Patents that are jointly-owned by Roche, and (Y) Brain Shuttle Collaboration Patents that are jointly or solely-owned by Roche or
                    its Affiliates, will count toward the calculation of the Full Royalty Period in a particular country if the use or sale of a Product by an unauthorized Third Party in such country would infringe a Valid Claim of such Licensed Patent or
                    Brain Shuttle Collaboration Patent.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="ze59d1e5ab793477584237bfd711af885">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Reduced Royalty Period</u></font><font style="font-size: 10pt;">. Subject to <u>Section 6.7.2(c)</u>, on a country-by-country and Product-by-Product basis,
                    after the expiration of the Full Royalty Period in a country and until the end of the Reduced Royalty Period, in lieu of the royalty rates set forth in <font style="font-variant: small-caps;"><u>Table 4</u></font> of <u>Section 6.7.1</u>,
                    Roche will pay Isis royalty rates (the &#8220;<font style="font-weight: bold; font-style: italic;">Roche Reduced Royalty</font>&#8221;) on Net Sales of Products in such country calculated on a Calendar Quarter-by-Calendar Quarter basis by [<font style="color: rgb(0, 0, 0);">***</font>]; <font style="font-style: italic;">provided, however</font>, that the Roche Reduced Royalty rate in each country will in no event exceed the Reference Rate applicable under this <u>Section
                      6.7</u>. For example, if peak Calendar Year Net Sales of a Product comprising an Isis Development Candidate during the Full Royalty Period were [<font style="color: rgb(0, 0, 0);">***</font>] and royalties paid for that same Calendar
                    Year were [<font style="color: rgb(0, 0, 0);">***</font>] resulting in a [<font style="color: rgb(0, 0, 0);">***</font>], and if [<font style="color: rgb(0, 0, 0);">***</font>] and the [<font style="color: rgb(0, 0, 0);">***</font>],
                    the applicable [<font style="color: rgb(0, 0, 0);">***</font>] in such country would be [<font style="color: rgb(0, 0, 0);">***</font>].&#160; Similarly, if the quarterly [<font style="color: rgb(0, 0, 0);">***</font>], then the applicable
                    [v] in such country would be [<font style="color: rgb(0, 0, 0);">***</font>].</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z7e84c2b0f6744f18a374a0e2312e89e6">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(c)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Limitation on Aggregate Reduction for Roche Royalties</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z883afcd1ec294386a31a72a4e287497a">

            <tr>
              <td style="width: 108pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(i)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>In no event will the aggregate royalty reductions under <u>Section 6.7.2(b)</u> and/or <u>Section 6.8</u> reduce the royalties payable to Isis on Net Sales of a Product in any given period to an amount that is less than the [<font style="color: rgb(0, 0, 0);">***</font>].</div>
              </td>
            </tr>

        </table>
        <div>&#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="z4327f7937e7a467c8c444b57fb77afae">

            <tr>
              <td style="width: 108pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(ii)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>In no event will the aggregate royalty offsets under <u>Section 6.11.3(b)</u> reduce the royalties payable to Isis on Net Sales of a Product in any given period to an amount that is less than the greater of (i) [<font style="color: rgb(0, 0, 0);">***</font>], and (ii) [<font style="color: rgb(0, 0, 0);">***</font>].</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">27</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z13cef70d82f04dafb2ab226c902b6dca">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(d)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>End of Royalty Obligation</u></font><font style="font-size: 10pt;">. On a country-by-country basis, other than [<font style="color: rgb(0, 0, 0);">***</font>],


                    Roche&#8217;s obligation to make royalty payments hereunder in such country will end on the expiration of the Reduced Royalty Period in such country. &#8220;<font style="font-weight: bold; font-style: italic;">Reduced Royalty Period</font>&#8221; means,
                    on a country by country basis, the period commencing upon the expiration of the [<font style="color: rgb(0, 0, 0);">***</font>] in such country and ending when the [v] (i) with respect to Net Sales of Products in Major Markets, [<font style="color: rgb(0, 0, 0);">***</font>], and (ii) [<font style="color: rgb(0, 0, 0);">***</font>].</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z907446c6f9354a11af042e1679487f3f">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(e)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Royalty Examples</u></font><font style="font-size: 10pt;">. <u><font style="font-variant: small-caps;">Schedule </font>6.7.2(e)</u> attached hereto
                    contains examples of how royalties will be calculated under this <u>Section 6.7</u>.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="ze6862158235946eea21ed91f51f0f9a7">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(f)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Allocation of Net Sales</u></font><font style="font-size: 10pt;">. If, by reason of one or more royalty rate adjustments under this <u>Section 6.7.2</u>,
                    different royalty rates apply to Net Sales of Products from different countries, Roche will [<font style="color: rgb(0, 0, 0);">***</font>] such Net Sales [<font style="color: rgb(0, 0, 0);">***</font><font style="font-variant: small-caps;"><u>]</u></font>. <u><font style="font-variant: small-caps;">Schedule </font>6.7.2(f)</u> attached hereto contains examples of how Net Sales of Products from different countries at different royalty rates will be [<font style="color: rgb(0, 0, 0);">***</font><font style="font-variant: small-caps;"><u>]</u></font>.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z9f61093d1f374f9b9e89bcfe5cc9aa0e">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.8.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Royalty Reduction Due to Decline In Product Sales Clearly Attributable to Sales of an [</u></font><font style="font-size: 10pt; font-weight: bold; color: rgb(0, 0, 0);"><u>***</u></font><font style="font-size: 10pt; font-weight: bold;"><u>].</u></font><font style="font-size: 10pt;"> If, after taking into account the then available data, including but not limited to epidemiology data, any
                    Third Party product sales and diagnostics sales data and relevant market research information, Roche determines (and provides written notice to Isis of such determination and the basis therefor) that any decline in sales of the AS
                    Development Candidate being Commercialized by Roche is clearly attributable to the sales of any [<font style="color: rgb(0, 0, 0);">***</font>], then, subject to <u>Section 6.7.2(c)(i)</u>, the royalty rates under <font style="font-variant: small-caps;"><u>Table</u></font><u> 4</u> applicable to such AS Development Candidate being Commercialized by Roche, its Affiliates or Sublicensees [<font style="color: rgb(0, 0, 0);">***</font>].&#160; For example, if
                    Roche determines such decline in sales to be [<font style="color: rgb(0, 0, 0);">***</font>], then Roche shall reduce royalties otherwise payable to Isis based on the actual Net Sales for that Calendar Quarter [<font style="color: rgb(0, 0, 0);">***</font>]. If Roche implements a royalty reduction under this <u>Section 6.8</u>, Roche will make such reductions with a one Calendar Quarter delay in order to generate the data and supporting calculations necessary
                    to determine the amount of any such reduction, and Roche shall include its calculation of such reduction in the applicable royalty report under <u>Section 6.12.2</u>. If Isis believes that any decline in sales of the AS Development
                    Candidate being Commercialized by Roche is not clearly attributable to the sales of any such [<font style="color: rgb(0, 0, 0);">***</font>], the Parties will discuss the matter in good faith and if the Parties cannot resolve such
                    matter it will be resolved in accordance with the dispute resolution process set forth in <u>Section 12.1</u>. Roche is not entitled to any royalty reduction under this <u>Section 6.8</u> as a result of sales of [<font style="color: rgb(0, 0, 0);">***</font>].</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z5cef734d40274c50aa53e9424b6bf7fc">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.9.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Apportionment of Compulsory Sublicensee Consideration</u></font><font style="font-size: 10pt;">. At such time as Roche or any of its Affiliates or
                    Sublicensees enters into a sublicense with a Compulsory Sublicensee, the Parties will discuss and mutually agree upon an adjustment of the royalty due to Isis under <u>Section 6.7</u> of this Agreement with respect to sales of Products
                    by such Compulsory Sublicensee, with such adjustment calculated based on a [<font style="color: rgb(0, 0, 0);">***</font>].</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zd6fc5414535f46989044ea6788e5ce81">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.10.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Reverse Royalty Payments to Roche for Discontinued Products</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">28</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z96f1d58e82374b82901023b35f1e27e3">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.10.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Reverse Royalty for a Discontinued Product Comprising an Isis Development Candidate</u></font><font style="font-size: 10pt;">. If Isis or any of its
                    Affiliates or Sublicensees Commercializes a Discontinued Product for which Roche has paid Isis the license fee under <u>Section 6.3</u> and such Discontinued Product (i) is comprised of an Isis Development Candidate, and (ii) was not
                    commercialized by Roche, its Affiliates or its Sublicensees, then following the First Commercial Sale of such Discontinued Product by Isis or its Affiliates or Sublicensees, Isis will pay Roche a royalty of [<font style="color: rgb(0, 0, 0);">***</font>] of Annual worldwide net sales of such Discontinued Product (&#8220;<font style="font-weight: bold; font-style: italic;">Isis Development Candidate Reverse</font><font style="font-weight: bold;">&#160;</font><font style="font-weight: bold; font-style: italic;">Royalties</font>&#8221;). Isis will pay Roche such Isis Development Candidate Reverse Royalties in accordance with the provisions governing payment of royalties from Roche to Isis in <u>Sections


                      6.7.2</u>, <u>6.11</u>, <u>6.12</u>, <u>6.13</u>, <u>6.14</u>, and <u>6.15</u> (<font style="font-style: italic;">mutatis mutandis</font>); <font style="font-style: italic;">provided, however</font>, that Isis&#8217; obligation to pay
                    Roche Isis Development Candidate Reverse Royalties will expire once Isis has paid Roche an amount equal to [<font style="color: rgb(0, 0, 0);">***</font>] for such Discontinued Product under <u>Section 6.2</u> and <u>Section 6.4</u>.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zb1105cebdf744e2aba5f9c25cd4c9add">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.10.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Reverse Royalty for a Discontinued Product Comprising a Brain Shuttle Development Candidate</u></font><font style="font-size: 10pt;">. If Roche has paid Isis
                    the license fee under <u>Section </u>6.3 and Isis or any of its Affiliates or Sublicensees Commercializes a Discontinued Product that is comprised of a Brain Shuttle Development Candidate, then following the First Commercial Sale of
                    such Discontinued Product by Isis or its Affiliates or Sublicensees, Isis will pay Roche a royalty of [<font style="color: rgb(0, 0, 0);">***</font>] of Annual worldwide net sales of such Discontinued Product (&#8220;<font style="font-weight: bold; font-style: italic;">Brain Shuttle Development Candidate Reverse</font><font style="font-weight: bold;">&#160;</font><font style="font-weight: bold; font-style: italic;">Royalties</font>&#8221;). Isis will pay Roche Brain Shuttle
                    Development Candidate Reverse Royalties in accordance with (and for the same duration as) the provisions governing payment of royalties from Roche to Isis in <u>Sections 6.7.2</u>, <u>6.11</u>, <u>6.12</u>, <u>6.13</u>, <u>6.14</u>,
                    and <u>6.15</u>, <font style="font-style: italic;">mutatis mutandis</font>.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z423f9109b0bb4b83a091e8bb8fd57591">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.11.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Third Party Payment Obligations</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z289826d161f44abc8d89359446421548">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.11.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Existing In-License Agreements</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zc4c80a47c5784103ae2c2301634c6314">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Isis&#8217; Existing In-License Agreements</u></font><font style="font-size: 10pt;">. Certain of the Licensed Technology Controlled by Isis as
                    of the Effective Date licensed to Roche under <u>Section </u><u>4.1.1</u> are in-licensed or were acquired by Isis under the agreements with Third Party licensors or sellers listed on <u><font style="font-variant: small-caps;">Schedule</font>&#160;6.11.1</u>
                    (such license or purchase agreements being the &#8220;<font style="font-weight: bold; font-style: italic;">Isis In-License Agreements</font>&#8221;), and certain milestone or royalty payments and license maintenance fees may become payable by Isis
                    to such Third Parties under the Isis In-License Agreements based on the Development or Commercialization of a Product by Roche under this Agreement. Any payment obligations arising under the Isis In-License Agreements as they apply to
                    Products that:</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div>
          <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z001d5068b1f1460d9d194fb9a30c635a" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

              <tr style="vertical-align: top;">
                <td style="width: 108pt;">&#160;</td>
                <td style="vertical-align: top; width: 36pt;">
                  <div style="text-align: justify;"><font style="font-weight: bold;">(i)</font></div>
                </td>
                <td style="vertical-align: top; width: auto;">
                  <div style="text-align: justify;">accrue prior to Option exercise, will be paid by [<font style="color: rgb(0, 0, 0);">***</font>] as [<font style="color: rgb(0, 0, 0);">***</font>]; and</div>
                </td>
              </tr>

          </table>
        </div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">29</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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" class="DSPFListTable" id="zfe68915a4aaf48b580974636ab6d2137" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

              <tr style="vertical-align: top;">
                <td style="width: 108pt;">&#160;</td>
                <td style="vertical-align: top; width: 36pt;">
                  <div style="text-align: justify;"><font style="font-weight: bold;">(ii)</font></div>
                </td>
                <td style="vertical-align: top; width: auto;">
                  <div style="text-align: justify;">accrue after Option exercise, will be paid by [v] as [<font style="color: rgb(0, 0, 0);">***</font>].</div>
                </td>
              </tr>

          </table>
        </div>
        <div>&#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="ze5c7111743884a7d83e7923f3144bc21">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Isis&#8217; Agreements at the time of Option Exercise</u>. </font><font style="font-size: 10pt;">Prior to Roche exercising the Option, Isis
                    shall disclose to Roche all agreements (other than the In-License Agreements) entered into after the Effective Date by Isis with Third Party licensors or sellers under which Isis licensed or acquired any Licensed Technology to be
                    licensed to Roche under <u>Section 4.1.1</u> (&#8220;<font style="font-weight: bold; font-style: italic;">Additional Isis In-License Agreements</font>&#8221;). Any payment obligations arising under any Additional Isis In-License Agreements as they
                    apply to Products that:</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div>
          <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z7195122a3f1f4f77ba61e821090c3983" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

              <tr style="vertical-align: top;">
                <td style="width: 108pt;">&#160;</td>
                <td style="vertical-align: top; width: 36pt;">
                  <div style="text-align: justify;"><font style="font-weight: bold;">(i)</font></div>
                </td>
                <td style="vertical-align: top; width: auto;">
                  <div style="text-align: justify;">accrue prior to Option exercise, will be paid by [<font style="color: rgb(0, 0, 0);">***</font>] as [<font style="color: rgb(0, 0, 0);">***</font>]; and</div>
                </td>
              </tr>

          </table>
        </div>
        <div>&#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="z317e3e0ecf0a408da79d47e9158beb28">

            <tr>
              <td style="width: 108pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(ii)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>accrue after Option exercise, will be paid by [<font style="color: rgb(0, 0, 0);">***</font>] as [<font style="color: rgb(0, 0, 0);">***</font>], in which case <u>Section 6.11.3</u> will apply.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z7441f29d6a2842c6b81b4f158ea8aeae">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(c)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Roche&#8217;s Existing In-License Agreements</u></font><font style="font-size: 10pt;">. Roche will be solely responsible for any Third Party
                    Obligations that become payable by Roche to Third Parties under any agreements or arrangements Roche has with such Third Parties as of the Effective Date, based on the Development or Commercialization of a Product by Roche, its
                    Affiliate or Sublicensee under this Agreement. Any such payment obligations will be paid by [<font style="color: rgb(0, 0, 0);">***</font>] as [<font style="color: rgb(0, 0, 0);">***</font>]<font style="color: rgb(255, 0, 0);">&#160;</font>under


                    this Agreement.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z1e6d5d9f21814436be61351b767f674a">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.11.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>New In-Licensed Product-Specific Patents</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z23aa23915a484f0c9f03023abdd13229">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>On a Product-by-Product basis, after Option exercise, Roche or Isis, as the case may be, will promptly provide the other Party written notice of any additional Third Party Patent Rights it has identified as necessary to Develop or
                  Commercialize a Product where such Third Party Patent Rights would be considered a Product-Specific Patent if either Party Controlled such Patent Rights (&#8220;<font style="font-weight: bold; font-style: italic;">Additional Product-Specific
                    Patents</font>&#8221;), and Roche will have the first right, but not the obligation, to negotiate with, and obtain a license from the Third Party Controlling such Additional Product-Specific Patents. If Roche obtains any such Additional
                  Product-Specific Patents then any financial obligations under such Third Party agreement will be paid solely by [<font style="color: rgb(0, 0, 0);">***</font>] as [<font style="color: rgb(0, 0, 0);">***</font>].</div>
              </td>
            </tr>

        </table>
        <div>&#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="z2a0deaf52ba54d6893e54367e6263002">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>If, however, Roche elects not to obtain such a license to such Additional Product-Specific Patents, Roche will so notify Isis, and Isis may obtain such a license to such Additional Product-Specific Patents and Isis will include such
                  Additional Product-Specific Patents in the license granted to Roche under <u>Section 4.1.1</u> provided that Roche agrees in writing to [<font style="color: rgb(0, 0, 0);">***</font>].</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">30</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z3fe9462e37b649b4b84cf45f4550f58d">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.11.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Additional Core IP In-License Agreements</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z17a038a37fb4442fa72ac2a8a23ae468">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Roche will promptly provide Isis written notice of any [<font style="color: rgb(0, 0, 0);">***</font>] (&#8220;<font style="font-weight: bold; font-style: italic;">Additional Core IP</font>&#8221;) that Roche believes it has identified and Isis
                  will have the first right, but not the obligation, to negotiate with, and obtain a license from the Third Party Controlling such Additional Core IP. For clarity, Additional Core IP does not include any Patent Rights claiming (or
                  intellectual property related to) [<font style="color: rgb(0, 0, 0);">***</font>]. If Isis obtains such a Third Party license, Isis will include such Additional Core IP in the license granted to Roche under <u>Section 4.1.1</u>, and any
                  financial obligations under such Third Party agreement will be paid solely by [<font style="color: rgb(0, 0, 0);">***</font>] as [<font style="color: rgb(0, 0, 0);">***</font>].</div>
              </td>
            </tr>

        </table>
        <div>&#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="zc0b760d5f1e34432a131cdcf5e0d7a04">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>If, however, Isis elects not to obtain such a license to such Third Party intellectual property, Isis will so notify Roche, and Roche may obtain such a Third Party license and, subject to <u>Section 6.7.2(c)(ii)</u>, Roche may offset
                  an amount equal to [<font style="color: rgb(0, 0, 0);">***</font>] of [<font style="color: rgb(0, 0, 0);">***</font>] paid by Roche under such Third Party license against any [<font style="color: rgb(0, 0, 0);">***</font><u>]</u> of this
                  Agreement in such country for [<font style="color: rgb(0, 0, 0);">***</font>].</div>
              </td>
            </tr>

        </table>
        <div>&#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="z5b19dcad05e445af8581a480cc943abb">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(c)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>If Isis does not agree with Roche that a license to such Third Party Patent Rights is necessary to [<font style="color: rgb(0, 0, 0);">***</font>], then Isis will send written notice to such effect to Roche, and the Parties will engage
                  a mutually agreed independent Third Party intellectual property lawyer with expertise in the patenting of ASOs, and appropriate professional credentials in the relevant jurisdiction, to determine the question of whether or not such Third
                  Party intellectual property is Additional Core IP. The determination of the Third Party expert engaged under the preceding sentence will be binding on the Parties solely for purposes of determining whether Roche is permitted to [<font style="color: rgb(0, 0, 0);">***</font>]. The costs of any Third Party expert engaged under this <u>Section 6.11.3(c)</u> will be paid by the Party against whose position the Third Party lawyer&#8217;s determination is made.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z3f75169c4ef44afcb8ddb4323e447fc7">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.12.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Payments</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z000cefc5df9647a3a53a9bc0982606cb">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.12.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Commencement</u></font><font style="font-size: 10pt;">. Beginning with the Calendar Quarter in which the First Commercial Sale, named patient sale,
                    compassionate use sale or other similar sales for a Product is made and for each Calendar Quarter thereafter, Roche will make royalty payments to Isis under this Agreement within [<font style="color: rgb(0, 0, 0);">***</font>] following
                    the end of each such Calendar Quarter.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z3e7e3bb191914a7ea962a4952d4eb33c">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.12.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Royalty Reporting</u></font><font style="font-size: 10pt;">. Each royalty payment will be accompanied by a report, summarizing in writing for the relevant
                    Calendar Quarter on a Product-by-Product basis the following information:</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z17efb302b3f746d0981c7f778ba386af">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Sales in Swiss Francs on a country-by-country basis;</div>
              </td>
            </tr>

        </table>
        <div>&#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="zfdc5eadb191246278e6f113cc8ae72a4">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Net Sales in Swiss Francs on a country-by-country basis;</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">31</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
        </div>
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            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(c)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Total worldwide Net Sales in Swiss Francs;</div>
              </td>
            </tr>

        </table>
        <div>&#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="z517b403c06c84f139284ae87b19826dd">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(d)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Exchange rate used for the conversion of Net Sales from Swiss Francs to US Dollars pursuant to <u>Section 6.12.4</u>;</div>
              </td>
            </tr>

        </table>
        <div>&#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="z3e966af3c951436c9251671e76029205">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(e)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Royalty Rate pursuant to <u>Section 2.1.1(b)(ii)</u> (if applicable), <u>Section 6.7.1</u> and <u>Section 6.7.2</u>, as applicable; and</div>
              </td>
            </tr>

        </table>
        <div>&#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="zf609ef9ae4f84b75814dbe3ec79507cb">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(f)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Total Royalty payable in US Dollars.</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="text-align: justify; margin-left: 36pt;">In addition, Roche will include in each report under this <u>Section </u>6.12.2 information regarding any Net Sales of Products sold for named patient, compassionate use or other similar sales
          and any consideration received from any Compulsory Sublicensees.</div>
        <div>&#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="z0aa816c9595b4899b19ea5da2cfd9854">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.12.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>After first Approval, if no royalties or other payments from Product sales are payable in respect of a given Calendar Quarter, Roche will submit a written royalty report to Isis so indicating together with an explanation as to why no
                  such royalties are payable. In addition, beginning with the Calendar Quarter in which the First Commercial Sale for a Product (or any named patient sale, compassionate use sale or other similar sales of a Product) is made and for each
                  Calendar Quarter thereafter, within ten (10) Business Days following the end of each such Calendar Quarter, Roche will provide Isis a [<font style="color: rgb(0, 0, 0);">***</font>] report estimating the total (A) Sales and Net Sales for
                  Products projected for such Calendar Quarter, and (B) if available, the amount of any consideration payable to Roche under sublicenses with Compulsory Sublicensees.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z58e55b85af6543acb205639fac6fa8aa">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.12.4.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Mode of Payment</u></font><font style="font-size: 10pt;">. All payments under this Agreement will be (i) payable in full in U.S. Dollars, regardless of the
                    country(ies) in which sales are made, (ii) made by wire transfer of immediately available funds to an account designated by Isis in writing, and (iii) irrevocable and non-refundable. Any corrections to calculations of royalty payments
                    previously paid shall be adjusted to the next royalty payment due. When calculating the Sales of a Product that occur in currencies other than U.S. Dollars, Roche will convert the amount of such sales into Swiss Francs and then into
                    U.S. Dollars using Roche&#8217;s then current internal foreign currency translation actually used on a consistent basis in preparing its audited financial statements (currently YTD average rate as reported by Reuters).</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zd0ba5f8900714f25b22336bf6a5bfde6">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.12.5.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Records Retention</u></font><font style="font-size: 10pt;">. Commencing with the First Commercial Sale or named patient sale of a Product, Roche will keep
                    complete and accurate records pertaining to the sale of Products for a period of [<font style="color: rgb(0, 0, 0);">***</font>] after the year in which such sales occurred, and in sufficient detail to permit Isis to confirm the
                    accuracy of the Net Sales or royalties paid by Roche hereunder.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">32</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z2c36d093145d4869a9b2368281267119">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.13.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Audits</u></font><font style="font-size: 10pt;">. After the first Approval of a Product, during the remaining Agreement Term and for a period of thirty-six
                    (36) calendar months thereafter, at the request and expense of Isis, Roche will permit an independent certified public accountant of internationally recognized standing appointed by Isis, at reasonable times and upon at least sixty (60)
                    Business Days written notice, but in no case more than once per Calendar Year, to examine such records as may be necessary for the purpose of verifying the calculation and reporting of Net Sales and the correctness of any royalty
                    payment made under this Agreement for any period within the preceding thirty-six (36) calendar months. No Calendar Year can be audited more than once.&#160; Any and all records of Roche examined by such independent certified public
                    accountant will be deemed Roche&#8217;s Confidential Information. The independent certified public accountant shall share all draft reports with Roche before the draft audit report is shared with Isis and before the final document is issued.
                    Upon completion of the audit, the accounting firm will provide both Roche and Isis with a written report disclosing whether the royalty payments made by Roche are correct and the specific details concerning any discrepancies (&#8220;<font style="font-weight: bold; font-style: italic;">Audit Report</font>&#8221;). If, as a result of any inspection of the books and records of Roche, it is shown that Roche&#8217;s payments under this Agreement were less than the royalty amount that
                    should have been paid, then Roche will make all payments required to be made by paying Isis the difference between such amounts to eliminate any discrepancy revealed by said inspection with the next royalty payment due, with interest
                    calculated in accordance with <u>Section 6.15</u>. If, as a result of any inspection of the books and records of Roche, it is shown that Roche&#8217;s payments under this Agreement were greater than the royalty amount that should have been
                    paid, then [<font style="color: rgb(0, 0, 0);">***</font>]. Isis will pay all fees charged by such accountant pursuant to the audit, <font style="font-style: italic;">except that</font>, if the audit determines that any additional
                    amounts payable by Roche for an audited period exceed [<font style="color: rgb(0, 0, 0);">***</font>] of the amount actually paid for such audited period, then, in addition to paying Isis any unpaid amounts discovered in such audit,
                    Roche will pay the fees and expenses charged by such accountant.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z8f642de14dca4c6894415d2a5921e16b">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.14.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Taxes</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z4432056dbd7747d28da23427b1f9f26e">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.14.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Taxes on Income</u></font><font style="font-size: 10pt;">. Each Party will be solely responsible for the payment of all taxes imposed on its share of income
                    arising directly or indirectly from the activities of the Parties under this Agreement.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z54fe340221254593ace4a0fb4dbe9cc4">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.14.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Withholding Tax</u></font><font style="font-size: 10pt;">. 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 able
                    to do so. In accordance with the procedures set forth in <u>Section 9.3</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.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">33</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="ze97d596ec5604343ad4ac79a60f4f0a0">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.14.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Tax Cooperation</u></font><font style="font-size: 10pt;">. At least fifteen (15) days 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 the Applicable Laws. 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 6.14</u>.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="text-align: justify; margin-left: 36pt;">The provisions of this <u>Section 6.14</u> are to be read in conjunction with the provisions of <u>Section 12.4</u> below.</div>
        <div>&#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="z0ea847a781304e2a933b2a431319f458">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">6.15.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Interest</u></font><font style="font-size: 10pt;">. Any undisputed payments to be made hereunder that are not paid on or before the date such payments are
                    due under this Agreement will bear interest at a rate per annum equal to the lesser of (i) one month LIBOR rate in effect on the date that such payment would have been first due plus two percentage points (2%) or (ii) the maximum rate
                    permissible under applicable law.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="text-align: center; font-weight: bold;">ARTICLE 7.</div>
        <div style="text-align: center; font-weight: bold;">INTELLECTUAL PROPERTY</div>
        <div>&#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="z6f28aa7d1981445eb82bc73bcc3bfd0d">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Ownership</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z11ec900376d94dd5bb8f73f901dc7b96">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.1.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Isis Technology and Roche Technology</u></font><font style="font-size: 10pt;">. As between the Parties, Isis will own and retain all of its rights, title and
                    interest in and to the Licensed Know-How and Licensed Patents and Roche will own and retain all of its rights, title and interest in and to the Roche Know-How and Roche Patents, subject to any assignments, rights or licenses expressly
                    granted by one Party to the other Party under this Agreement.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zb41fd51296594583bb01740146918cc9">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.1.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Agreement Technology</u></font><font style="font-size: 10pt;">. Each Party will promptly disclose to the other Party in writing, and will cause its
                    Affiliates to so disclose, the discovery, development, or creation of any invention made solely or jointly by the Parties in connection with the performance of obligations under this Agreement. Except as expressly provided in this
                    Agreement, neither Party will have any obligation to account to the other for profits with respect to, or to obtain any consent of the other Party to license or exploit, Jointly-Owned Collaboration Technology by reason of joint
                    ownership thereof, and each Party hereby waives any right it may have under the laws of any jurisdiction to require any such consent or accounting.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">34</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z4d661bf3476d47f0aba6d469a5545d73">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.1.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Joint Patent Committee</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zbf8a75e20a084f4aae209235c699baa8">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>The Parties will establish a &#8220;<font style="font-weight: bold; font-style: italic;">Joint Patent Committee</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">JPC</font>.&#8221; The JPC will serve as the primary contact and forum
                  for discussion between the Parties with respect to intellectual property matters arising under this Agreement, and will cooperate with respect to the activities set forth in this <u>ARTICLE 7</u>. Isis&#8217; obligation to
                  participate in the JPC will terminate upon the date Isis is no longer obligated to participate in the JSC. Thereafter, Isis will have the right, but not the obligation, to participate in JPC meetings. The JPC determines the invention
                  classification for each invention arising under this Agreement. The classifications are (i) Brain Shuttle Collaboration Patents, (ii) Isis Product-Specific Patents, (iii) Jointly-Owned Collaboration Patents, (iv) Isis Core Technology
                  Patents, and (v) Isis Manufacturing and Analytical Patents. In addition, with respect to the Brain Shuttle Collaboration Patents classification, the JPC will determine the following sub-categories of Brain Shuttle Collaboration Patents:
                  (w) Patent Rights claiming inventions solely related to the Brain Shuttle Technology (&#8220;<font style="font-weight: bold; font-style: italic;">Brain Shuttle-Specific Collaboration Patents</font>&#8221;); (x) Patent Rights claiming inventions
                  solely related to ASOs that do not utilize the Brain Shuttle Technology (&#8220;<font style="font-weight: bold; font-style: italic;">ASO-Specific Collaboration Patents</font>&#8221;); (y) Patent Rights claiming inventions solely related to the
                  linking or conjugation of molecules (&#8220;<font style="font-weight: bold; font-style: italic;">Linker-Specific Collaboration Patents</font>&#8221;); and (z) Patent Rights claiming more than one of the technologies described in items (w) through (y)
                  above (&#8220;<font style="font-weight: bold; font-style: italic;">Omnibus Collaboration Patents</font>&#8221;). The JPC will endeavor to separate the claims within such Patent Rights into separate and distinct patent applications corresponding with
                  the categories and sub-categories described in this <u>Section 7.1.3(a)</u> to the extent possible without diminishing the patentability of the inventions.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z4c9a7399df5f45b69d5588e23eab68ed">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>A strategy will be discussed with regard to (x) prosecution and maintenance, defense and enforcement of (A) Brain Shuttle Collaboration Patents, (B) Isis Product-Specific Patents, and (C) Jointly-Owned Collaboration Patents licensed to
                  Roche under <u>Section 4.1.1</u> in connection with a Product, (y) defense against allegations of infringement of Third Party Patent Rights, and (z) licenses to Third Party Patent Rights or Know-How (including whether to obtain any
                  licenses under any such Third-Party Patent Rights or Know-How, and whether there are any known Third Party Obligations applicable to a particular Product), in each case to the extent such matter would be reasonably likely to have a
                  material impact on the Agreement or the licenses granted hereunder, which strategy will be considered in good faith by the Party entitled to prosecute, enforce and defend such Patent Rights hereunder, but will not be binding on such
                  Party.&#160; Notwithstanding the above, subject to the provisions of <u>Section 6.11</u>, Roche shall have final say as to whether to obtain any licenses under Third-Party Patent Rights or Know-How.</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">35</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z1ab801414b0641caa2c719314bc51bd0">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(c)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>In addition, the Joint Patent Committee will be responsible for the determination of inventorship. The determination of inventorship will be in accordance with United States patent laws and therefore will determine if the invention is
                  solely or jointly owned by the relevant Party or Parties. In case of a dispute in the Joint Patent Committee (or otherwise between Isis and Roche) over inventorship or classification, if the Joint Patent Committee cannot resolve such
                  dispute, even after seeking the JSC&#8217;s input, such dispute will be resolved by independent patent counsel not engaged or regularly employed in the past two years by either Party and reasonably acceptable to both Parties. The decision of
                  such independent patent counsel will be binding on the Parties. Expenses of such patent counsel will be shared equally by the Parties.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z14ec4347d3f64f089a349b6c7bd8dfea">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(d)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>The JPC will comprise an equal number of members from each Party. The Joint Patent Committee will meet as often as agreed by them (and at least semi-Annually), to discuss matters arising out of the activities set forth in this <u>ARTICLE


                    7</u>. The JPC will determine by unanimous consent the JPC operating procedures at its first meeting. To the extent reasonably requested by either Party, the Joint Patent Committee will solicit the involvement of more senior members of
                  their respective legal departments with respect to critical issues. Each Party&#8217;s representatives on the Joint Patent Committee will consider comments and suggestions made by the other in good faith. If either Party deems it reasonably
                  advisable, the Parties will enter into a mutually agreeable common interest agreement covering the matters contemplated by this Agreement.</div>
              </td>
            </tr>

        </table>
        <div>&#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="zb4ab6736043c42038a7ef17bb0645cdc">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Prosecution and Maintenance of Patents</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zccefd88bd83b4b82adbe6bc8c97bd38c">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.2.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Patent Filings</u></font><font style="font-size: 10pt;">. The Party responsible for Prosecution and Maintenance of any Patent Rights as set forth in <u>Section


                      7.2.2</u> and <u>Section 7.2.3</u> will endeavor to obtain patent protection for a Product as it Prosecutes and Maintains its other patents Covering products in development, using counsel of its own choice but reasonably acceptable
                    to the other Party, in such countries as the responsible Party sees fit.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zb96d3259582c4476948322816e1242b3">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.2.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Licensed Patents and Roche Patents</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z99f1f89f73c5435fa9247d7de5c7a16c">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Licensed Patents</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zc75aa544fca84c1ea5d7f79d3142db1d">

            <tr>
              <td style="width: 108pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(i)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Isis Core and Manufacturing Patents</u></font><font style="font-size: 10pt;">. Isis will at all times control and be responsible for all aspects of (i) any
                    Brain Shuttle Collaboration Patents solely-owned by Isis that (A) include claims that are directed to subject matter applicable to ASOs in general, or (B) include an ASO, the sequence of which targets the RNA that encodes HTT and ASOs
                    that do not target the RNA encoding HTT (each, an &#8220;<font style="font-weight: bold; font-style: italic;">Isis Core Brain Shuttle Collaboration Patent</font>&#8221;), (ii) the Isis Core Technology Patents, and (iii) the Isis Manufacturing and
                    Analytical Patents.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">36</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z775365c775464e74910c2edfc03e6251">

            <tr>
              <td style="width: 108pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(ii)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Isis Product-Specific Patents</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div>
          <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z4e7b3d9b10a94e289467728c679179c9" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

              <tr style="vertical-align: top;">
                <td style="width: 108pt;">&#160;</td>
                <td style="vertical-align: top; width: 36pt;">
                  <div style="text-align: justify;"><font style="font-weight: bold;">(1)</font></div>
                </td>
                <td style="vertical-align: top; width: auto;">
                  <div style="text-align: justify;"><font style="font-weight: bold; font-style: italic;"><u>Before Option Exercise</u></font>. Before Option exercise, subject to <u>Section 7.2.3</u> and <u>Section 7.2.4</u>, at Isis&#8217; expense, Isis will
                    control and be responsible for all aspects of the Prosecution and Maintenance of all (x) Brain Shuttle Collaboration Patents solely-owned by Isis that are necessary or useful to Develop or Commercialize a Product eligible to be licensed
                    to Roche under <u>Section 4.1.1</u> and <font style="font-style: italic;"><u>are not</u></font> necessary or useful to develop or commercialize products that are not Products (each, an &#8220;<font style="font-weight: bold; font-style: italic;">Isis Product-Specific Brain Shuttle Collaboration Patent</font>&#8221;), and (y) Isis Product-Specific Patents, and will use commercially reasonably efforts to Prosecute and Maintain such Patent Rights.</div>
                </td>
              </tr>

          </table>
        </div>
        <div>&#160;</div>
        <div>
          <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z9c7767618abc4d1aaf756dce32f7fc92" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

              <tr style="vertical-align: top;">
                <td style="width: 108pt;">&#160;</td>
                <td style="vertical-align: top; width: 36pt;">
                  <div style="text-align: justify;"><font style="font-weight: bold;">(2)</font></div>
                </td>
                <td style="vertical-align: top; width: auto;">
                  <div style="text-align: justify;"><font style="font-weight: bold; font-style: italic;"><u>After Option Exercise</u></font>. After Option exercise, subject to <u>Section 7.2.3</u> and <u>Section 7.2.4</u>, at Roche&#8217;s expense, Roche will
                    control and be responsible for all aspects of the Prosecution and Maintenance of all Isis Product-Specific Brain Shuttle Collaboration Patents and Isis Product-Specific Patents Covering Products licensed to Roche under <u>Section 4.1.1</u>
                    and will either (i) use commercially reasonably efforts to Prosecute and Maintain such Patent Rights or (ii) offer to assign Roche&#8217;s entire right, title and interest in such Patent Rights to Isis, in which case following any such
                    assignment all licenses granted in this Agreement by Isis to Roche under such Patent Rights shall become non-exclusive and the exclusivity covenants under <u>Section 2.1.1</u> will no longer apply to such Patent Rights.</div>
                </td>
              </tr>

          </table>
        </div>
        <div>&#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="zb06c1e651d0a46d782c74cb8cc3fe366">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Roche Patents and Roche Brain Shuttle Collaboration Patents</u></font><font style="font-size: 10pt;">. Roche will control and be responsible for all aspects
                    of the Prosecution and Maintenance of all (i) Brain Shuttle Collaboration Patents solely-owned by Roche, and (ii) Roche Patents, subject to <u>Section 7.2.3</u> and <u>Section 7.2.4</u>.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z8f9e214b788c448db6da406c03d09355">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.2.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Jointly-Owned Collaboration Patents</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z408abe81cd4249788b05a2e72de12dc3">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Before Option Exercise</u></font><font style="font-size: 10pt;">. Before Option exercise, (i) Isis will control and be responsible for
                    all aspects of the Prosecution and Maintenance of Jointly-Owned Collaboration Patents Covering Isis Development Candidates, and (ii) Roche will control and be responsible for all aspects of the Prosecution and Maintenance of any
                    Jointly-Owned Collaboration Patents Covering Brain Shuttle Development Candidates.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">37</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="zbe689081cfb7409c9909137776502b71">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>After Option Exercise</u></font><font style="font-size: 10pt;">. After Option exercise, Roche will control and be responsible for all
                    aspects of the Prosecution and Maintenance of (i) Jointly-Owned Collaboration Patents Covering Products, and (ii) jointly-owned Brain Shuttle Collaboration Patents, and will either (y) use commercially reasonably efforts to Prosecute
                    and Maintain such Patent Rights or (z) offer to assign Roche&#8217;s entire right, title and interest in such Patent Rights to Isis, in which case following any such assignment all licenses granted in this Agreement by Isis to Roche under
                    such Patent Rights shall become non-exclusive and the exclusivity covenants under <u>Section 2.1.1</u> will no longer apply to such Patent Rights.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zf326cf13988642f59ea1ca6d496eb728">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.2.4.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Other Matters Pertaining to Prosecution and Maintenance of Patents</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zc805749704224232b145593edc508db9">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Each Party will keep the other Party informed through the Joint Patent Committee as to material developments with respect to the Prosecution and Maintenance of the Product-Specific Patents or Jointly-Owned Collaboration Patents for
                  which such Party has responsibility for Prosecution and Maintenance pursuant to <u>Section 7.2.2</u>, <u>Section 7.2.3</u> or this <u>Section 7.2.4</u>, including by providing copies of material data as it arises, any office actions or
                  office action responses or other correspondence that such Party provides to or receives from any patent office, including notice of all interferences, reissues, re-examinations, 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>
              </td>
            </tr>

        </table>
        <div>&#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="za65bd17e2ef64c8387244b318d940a92">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>If Roche elects (a) not to file and prosecute patent applications for the Jointly-Owned Collaboration Patent or Isis Product-Specific Patents that have been licensed to Roche under this Agreement or the Brain Shuttle Collaboration
                  Patents for which Roche has responsibility for Prosecution and Maintenance pursuant to <u>Section 7.2.2</u> or <u>Section 7.2.3</u> (&#8220;<font style="font-weight: bold; font-style: italic;">Roche-Prosecuted Patents</font>&#8221;) in a particular
                  country, (b) not to continue the prosecution (including any interferences, oppositions, reissue proceedings, re-examinations, and patent term extensions, adjustments, and restorations) or maintenance of any Roche-Prosecuted Patent in a
                  particular country, or (c) not to file and prosecute patent applications for the Roche-Prosecuted Patent in a particular country following a written request from Isis to file and prosecute in such country, then Roche will so notify Isis
                  promptly in writing of its intention in good time to enable Isis to meet any deadlines by which an action must be taken to establish or preserve any such Patent Right in such country; and Isis will have the right, but not the obligation,
                  to file, prosecute, maintain, enforce, or otherwise pursue such Roche-Prosecuted Patent in the applicable country at its own expense with counsel of its own choice. In such case, Roche will cooperate with Isis to file for, or continue to
                  Prosecute and Maintain or enforce, or otherwise pursue such Roche-Prosecuted Patent in such country in Isis&#8217; own name. Notwithstanding anything to the contrary in this Agreement, if Isis assumes responsibility for the Prosecution and
                  Maintenance of any such Roche-Prosecuted Patent under this <u>Section 7.2.4(b)</u>, Isis will have no obligation to notify Roche if Isis intends to abandon such Roche-Prosecuted Patent. The analogous situation shall apply <font style="font-style: italic;">mutatis mutandis</font> with regard to Patent Rights (excluding Isis Core Technology Patents and Isis Manufacturing and Analytical Patents) for which Isis has responsibility for Prosecution and Maintenance
                  pursuant to <u>Section 7.2.2</u> or <u>Section 7.2.3</u>.</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">38</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z6fe476db4ea249bd83bbead5ff0c3e14">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(c)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>The Parties, through the Joint Patent Committee, will cooperate in good faith to determine if and when any divisional or continuation applications will be filed with respect to any Jointly-Owned Collaboration Patents or
                  Product-Specific Patents, and where a divisional or continuation patent application filing would be practical and reasonable, then such a divisional or continuation filing will be made.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z4758c98b99da45789df95ba383ad82f2">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(d)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>If the Party responsible for Prosecution and Maintenance pursuant to <u>Section 7.2.3</u> intends to abandon such Jointly-Owned Collaboration Patent without first filing a continuation or substitution, then such Party will notify the
                  other Party of such intention at least sixty (60) days before such Jointly-Owned Collaboration Patent will become abandoned, and such other Party will have the right, but not the obligation, to assume responsibility for the Prosecution
                  and Maintenance thereof at its own expense (subject to <u>Section 7.3.1)</u> with counsel of its own choice, in which case the abandoning Party will, and will cause its Affiliates to, assign to the other Party (or, if such assignment is
                  not possible, grant a fully-paid exclusive license in) all of their rights, title and interest in and to such Jointly-Owned Collaboration Patents. If a Party assumes responsibility for the Prosecution and Maintenance of any such
                  Jointly-Owned Collaboration Patents under this <u>Section 7.2.4(d)</u>, such Party will have no obligation to notify the other Party of any intention of such Party to abandon such Jointly-Owned Collaboration Patents.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z9bfb48eab3d74f86be19d4c79784e7c0">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(e)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>In addition, the Parties will consult, through the Joint Patent Committee, and take into consideration the comments of the other Party for all matters relating to interferences, reissues, re-examinations and oppositions with respect to
                  those Patent Rights in which such other Party (i) has an ownership interest, (ii) has received a license thereunder in accordance with this Agreement, or (iii) may in the future, in accordance with this Agreement, obtain a license or
                  sublicense thereunder.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z08381e503f804186ad356640038e2219">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Patent Costs</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">39</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z21c073598a0b4434af73ed2c9f2069b1">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.3.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Jointly-Owned Collaboration Patents</u></font><font style="font-size: 10pt;">. Unless the Parties agree otherwise, Isis and Roche will share equally the
                    Patent Costs associated with the Prosecution and Maintenance of Jointly-Owned Collaboration Patents; <font style="font-style: italic;">provided that</font>, either Party may decline to pay its share of costs for filing, prosecuting and
                    maintaining any Jointly-Owned Collaboration Patents in a particular country or particular countries, in which case the declining Party will, and will cause its Affiliates to, assign to the other Party (or, if such assignment is not
                    possible, grant a fully-paid exclusive license in) all of their rights, titles and interests in and to such Jointly-Owned Collaboration Patents.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z426058b59e29472cb786a1d3fe7fe405">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.3.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Licensed Patents and Roche Patents</u></font><font style="font-size: 10pt;">. Except as set forth in <u>Section 7.2.4</u> and <u>Section 7.3.1</u>, each
                    Party will be responsible for all Patent Costs incurred by such Party prior to and after the Effective Date in all countries in the Prosecution and Maintenance of Patent Rights for which such Party is responsible under <u>Section 7.2</u>;
                    <font style="font-style: italic;">provided, however</font>, that after Option exercise, Roche will be solely responsible for Patent Costs arising from the Prosecution and Maintenance of the Isis Product-Specific Patents; <font style="font-style: italic;">provided that</font>, Roche may decline to pay for filing, prosecuting and maintaining any Isis Product-Specific Patents in a particular country or particular countries, in which case all licenses granted
                    in this Agreement by Isis to Roche under such Patent Rights shall become non-exclusive and the exclusivity covenants under <u>Section 2.1.1</u> will no longer apply to such Patent Rights.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z7461bd8ec03540018816cea0e231b31e">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.4.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Defense of Claims Brought by Third </u><u>Parties</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z7f57dce4c86d488cb1064788fac8872b">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.4.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>If a Third Party initiates a Proceeding claiming a Patent Right owned by or licensed to such Third Party is infringed by the Development, Manufacture or Commercialization of a Product, (a) Isis will have the first right, but not the
                  obligation, to defend against any such Proceeding initiated prior to Option exercise at its sole cost and expense and (b) Roche will have the first right, but not the obligation, to defend against any such Proceeding initiated after
                  Option exercise at its sole cost and expense. If the Party having the first right to defend against such Proceeding (the &#8220;<font style="font-weight: bold; font-style: italic;">Lead Party</font>&#8221;) elects to defend against such Proceeding,
                  then the Lead Party will have the sole right to direct the defense and to elect whether to settle such claim (but only with the prior written consent of the other Party, not to be unreasonably withheld, conditioned or delayed). The other
                  Party will reasonably assist the Lead Party in defending such Proceeding and cooperate in any such litigation at the request and expense of the Lead Party. The Lead Party will provide the other Party with prompt written notice of the
                  commencement of any such Proceeding that is of the type described in this <u>Section 7.4</u>, and the Lead Party will keep the other Party apprised of the progress of such Proceeding. If the Lead Party elects not to defend against a
                  Proceeding, then the Lead Party will so notify the other Party in writing within sixty (60) days after the Lead Party first receives written notice of the initiation of such Proceeding, and the other Party (the &#8220;<font style="font-weight: bold; font-style: italic;">Step-In Party</font>&#8221;) will have the right, but not the obligation, to defend against such Proceeding at its sole cost and expense and thereafter the Step-In Party will have the sole right to direct the
                  defense thereof, including the right to settle such claim. In any event, the Party not defending such Proceeding will reasonably assist the other Party and cooperate in any such litigation at the request and expense of the Party defending
                  such Proceeding.&#160; 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 7.4</u>. Each Party will provide the other Party with prompt written notice of
                  the commencement of any such Proceeding under this <u>Section 7.4</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>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">40</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z30db24996cee42798639e4d20e31509c">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.4.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Discontinued Product</u></font><font style="font-size: 10pt;">. If a Third Party initiates a Proceeding claiming that any Patent Right or Know-How owned by
                    or licensed to such Third Party is infringed by the Development, Manufacture or Commercialization of a Discontinued Product, Isis will have the first right, but not the obligation, to defend against and settle such Proceeding at its
                    sole cost and expense. Roche will reasonably assist Isis in defending such Proceeding and cooperate in any such litigation at the request and expense of Isis.&#160; Each Party may at its own expense and with its own counsel join any defense
                    directed by the other Party. Isis will provide Roche with prompt written notice of the commencement of any such Proceeding, or of any allegation of infringement of which Isis becomes aware and that is of the type described in this <u>Section


                    </u><u>7.4.2</u>, and Isis will promptly furnish Roche with a copy of each communication relating to the alleged infringement received by Isis.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z190954feac364cf5a35c33e1f68dc4f6">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.4.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Interplay Between Enforcement of IP and Defense of Third Party Claims</u></font><font style="font-size: 10pt;">.&#160;&#160; Notwithstanding the provisions of <u>Section


                      7.4.1</u> and <u>Section 7.4.2</u>, to the extent that a Party&#8217;s defense against a Third Party claim of infringement under this <u>Section 7.4</u> involves (i) the enforcement of the other Party&#8217;s Know-How or Patent Rights, or (ii)
                    the defense of an invalidity claim with respect to such other Party&#8217;s Know-How or Patent Rights, then, in each case, the general concepts of <u>Section 7.5</u> will apply to the enforcement of such other Party&#8217;s Know-How or Patent
                    Rights or the defense of such invalidity claim (<u>i.e.</u>, each Party has the right to enforce its own intellectual property, except that the relevant Commercializing Party will have the initial right, to the extent provided in <u>Section


                      7.5</u>, to enforce such Know-How or Patent Rights or defend such invalidity claim, and the other Party will have a step-in right, to the extent provided in <u>Section 7.5</u>, to enforce such Know-How or Patent Rights or defend such
                    invalidity claim).</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zfe96147c169940d1916a7973922bbff7">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.5.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Enforcement of Patents Against Competitive Infringement</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z869c7cd5bfae4a9f95479a979d5fbed5">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.5.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Duty to Notify of Competitive Infringement</u></font><font style="font-size: 10pt;">. If either Party learns of an infringement, unauthorized use,
                    misappropriation or threatened infringement by a Third Party to which such Party does not owe any obligation of confidentiality with respect to any Product-Specific Patents by reason of the development, manufacture, use or
                    commercialization of a product directed against the RNA that encodes HTT in the Field (&#8220;<font style="font-weight: bold; font-style: italic;">Competitive</font><font style="font-style: italic;">&#160;</font><font style="font-weight: bold; font-style: italic;">Infringement</font>&#8221;), 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 7.5.7</u> below, such written notice will be given within ten (10) Business Days.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">41</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z351cd7576f7645fcba15859777e03bea">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.5.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Prior to Option Exercise</u></font><font style="font-size: 10pt;">.<font style="font-weight: bold;">&#160;</font>For any Competitive Infringement occurring after
                    the Effective Date but before Option exercise, Isis will have the first right, but not the obligation, to institute, prosecute, and control a Proceeding with respect thereto, by counsel of its own choice, and Roche will have the right
                    to be represented in that action by counsel of its own choice at its own expense, <font style="font-style: italic;">however</font>, Isis will have the sole right to control such litigation. Isis will provide Roche with prompt written
                    notice of the commencement of any such Proceeding, and Isis will keep Roche apprised of the progress of such Proceeding. If Isis fails to initiate a Proceeding within a period of ninety (90) days after receipt of written notice of such
                    Competitive Infringement (subject to a ninety (90) day extension to conclude negotiations, which extension will apply only in the event that Isis has commenced good faith negotiations with an alleged infringer for elimination of such
                    Competitive Infringement within such ninety (90) day period), Roche will have the right to initiate and control a Proceeding with respect to such Competitive Infringement by counsel of its own choice; <font style="font-style: italic;">provided


                      that</font> Isis will have the right to be represented in any such action by counsel of its own choice at its own expense. Notwithstanding the foregoing, Isis will at all times have the sole right to institute, prosecute, and control
                    any Proceeding under this <u>Section 7.5.2</u> to the extent involving any Isis Core Technology Patents or Isis Manufacturing and Analytical Patents.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z278b25d784364a9184e8e581b6c331fc">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.5.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Following Option Exercise</u></font><font style="font-size: 10pt;">. For any Competitive Infringement with respect to a Product (except for a Discontinued
                    Product) occurring after Option exercise, so long as part of such Proceeding Roche also enforces any Patent Rights Controlled by Roche being infringed that Cover a Product, then Roche will have the first right, but not the obligation,
                    to institute, prosecute, and control a Proceeding with respect thereto by counsel of its own choice at its own expense, and Isis will have the right, at its own expense, to be represented in that action by counsel of its own choice, <font style="font-style: italic;">however,</font> Roche will have the right to control such litigation. If Roche fails to initiate a Proceeding within a period of ninety (90) days after receipt of written notice of such Competitive
                    Infringement (subject to a ninety (90) day extension to conclude negotiations, if Roche has commenced good faith negotiations with an alleged infringer for elimination of such Competitive Infringement within such ninety (90) day
                    period), Isis will have the right to initiate and control a Proceeding with respect to such Competitive Infringement by counsel of its own choice, and Roche will have the right to be represented in any such action by counsel of its own
                    choice at its own expense. Notwithstanding the foregoing, Isis will at all times have the sole right to institute, prosecute, and control any Proceeding under this <u>Section 7.5.3</u> to the extent involving any Isis Core Technology
                    Patents or Isis Manufacturing and Analytical Patents.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z7b2b547e1ba0415aaf7785e7df94e74a">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.5.4.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Joinder</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">42</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="za13efe46c87c4bcda46790a5c93a65de">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>If a Party initiates a Proceeding in accordance with this <u>Section 7.5</u>, 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 7.5.5</u>, the costs and expenses of each Party incurred pursuant to this <u>Section 7.5.4(a)</u> will be borne by the Party initiating such Proceeding.</div>
              </td>
            </tr>

        </table>
        <div>&#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="zcd139f9b157a4f50a22b907e3b03c0f9">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>If one Party initiates a Proceeding in accordance with this <u>Section 7.5.4</u>, 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>
              </td>
            </tr>

        </table>
        <div>&#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="ze0a05646f3a1482691354d5a97cf4e52">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.5.5.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Share of Recoveries</u></font><font style="font-size: 10pt;">. Any damages or other monetary awards recovered with respect to a Proceeding brought pursuant
                    to this <u>Section 7.5</u> will be shared as follows:</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z99ebd854bd4e425f8cc96a1b5c83b653">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>the amount of such recovery will first be applied to the Parties&#8217; reasonable out-of-pocket costs incurred in connection with such Proceeding (which amounts will be allocated <font style="font-style: italic;">pro rata</font> if
                  insufficient to cover the totality of such expenses); then</div>
              </td>
            </tr>

        </table>
        <div>&#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="zad954b6efe9648088251099ce3d65dac">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>any remaining proceeds constituting direct or actual damages for acts of infringement occurring prior to Roche&#8217;s exercise of the Option will be (i) [<font style="color: rgb(0, 0, 0);">***</font>]; or (ii) [<font style="color: rgb(0, 0, 0);">***</font>]; then</div>
              </td>
            </tr>

        </table>
        <div>&#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="za04a6d6756e147a4a440b65c0daa3522">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(c)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>any remaining proceeds constituting direct or actual damages for acts of infringement occurring after Roche&#8217;s exercise of the Option will be treated [<font style="color: rgb(0, 0, 0);">***</font>], and [<font style="color: rgb(0, 0, 0);">***</font>]; then</div>
              </td>
            </tr>

        </table>
        <div>&#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="z016ae5c570e54b6db02f0084bf4d5c1e">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(d)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>any remaining proceeds constituting punitive or treble damages will be allocated between the Parties as follows: the Party initiating the Proceeding will receive and retain [<font style="color: rgb(0, 0, 0);">***</font>] of such
                  proceeds and the other Party will receive and retain [<font style="color: rgb(0, 0, 0);">***</font>] of such proceeds.</div>
              </td>
            </tr>

        </table>
        <div>&#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="zea938335c5944925b763d821fb791fd0">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.5.6.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Settlement</u></font><font style="font-size: 10pt;">. Notwithstanding anything to the contrary under this <u>ARTICLE 7</u>, neither Party may enter a
                    settlement, consent judgment or other voluntary final disposition of a suit under this <u>ARTICLE 7</u> that 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 without first obtaining the written consent of the Party that Controls the relevant Patent Right.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z9e06df8c05b346ecaee2968b6f8d9417">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.5.7.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>35 USC 271(e)(2) Infringement</u></font><font style="font-size: 10pt;">. Notwithstanding anything to the contrary in this <u>Section 7.5</u>, solely with
                    respect to Licensed Patents, for a Competitive Infringement under 35 USC 271(e)(2), the time period set forth in <u>Section 7.5.2</u> during which a Party will have the initial right to bring a Proceeding will be shortened to a total
                    of twenty-five (25) days, so that, to the extent the other Party has the right, pursuant to such Section to initiate a Proceeding if the first Party does not initiate a Proceeding, such other Party will have such right if the first
                    Party does not initiate a Proceeding within twenty-five (25) days after such first Party&#8217;s receipt of written notice of such Competitive Infringement.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">43</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="zf5e70638597f4f2c9bf7c6dc074eca4b">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.6.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Other Infringement</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zf62abea29f7c435a976b8c6ece9059fe">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.6.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Jointly-Owned Collaboration Patents</u></font><font style="font-size: 10pt;">. With respect to the infringement of a Jointly-Owned Collaboration Patent which
                    is not a Competitive Infringement, the Parties will cooperate in good faith to bring suit together against such infringing party or the Parties may decide to permit one Party to solely bring suit. Any damages or other monetary awards
                    recovered with respect to a Proceeding brought pursuant to this <u>Section 7.6.1</u> will be shared as follows: (i) the amount of such recovery will first be applied to the Parties&#8217; reasonable out-of-pocket costs incurred in connection
                    with such Proceeding (which amounts will be allocated <font style="font-style: italic;">pro rata</font> if insufficient to cover the totality of such expenses); (ii) any remaining proceeds constituting direct damages will be [<font style="color: rgb(0, 0, 0);">***</font>], and (iii) any remaining proceeds constituting punitive or treble damages will be allocated as follows: (A) if the Parties jointly initiate a Proceeding pursuant to this <u>Section 7.6.1</u>,
                    [<font style="color: rgb(0, 0, 0);">***</font>] of such proceeds; and (B) if only one Party initiates the Proceeding pursuant to this <u>Section 7.6.1</u>, such Party will receive [<font style="color: rgb(0, 0, 0);">***</font>] of such
                    proceeds and the other Party will receive [<font style="color: rgb(0, 0, 0);">***</font>] of such proceeds.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="za11ff3fba2ca47038688d7cb3de63e26">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.6.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Patents Solely Owned by Isis</u></font><font style="font-size: 10pt;">. Isis will retain all rights to pursue an infringement of any Patent Right solely
                    owned by Isis which is other than a Competitive Infringement and Isis will retain all recoveries with respect thereto.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z4f45d441d3264f06b8c37ecd7ff8949c">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.6.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Patents Solely Owned by Roche</u></font><font style="font-size: 10pt;">. Roche will retain all rights to pursue an infringement of any Patent Right solely
                    owned by Roche which is other than a Competitive Infringement and Roche will retain all recoveries with respect thereto.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z04cd3f0e48af4c9ba721569fa2eb9b36">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.7.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Patent Listing</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z20956e10a63a4186a9e5adcf050b13c7">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.7.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Roche&#8217;s Obligations</u></font><font style="font-size: 10pt;">. Roche will promptly, accurately and completely list, with the applicable Regulatory
                    Authorities during the Agreement Term, all applicable Patent Rights that Cover a Product.&#160; Prior to such listings, the Parties will meet, through the Joint Patent Committee, to evaluate and identify all applicable Patent Rights, and
                    Roche will have the right to review, where reasonable, original records relating to any invention for which Patent Rights are being considered by the Joint Patent Committee for any such listing. Notwithstanding the preceding sentence,
                    Roche will retain final decision-making authority as to the listing of all applicable Patent Rights for a Product that are not Isis Core Technology Patents or Isis Manufacturing and Analytical Patents, regardless of which Party owns
                    such Patent Rights.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">44</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z76f4794a00034041bc319e6f9e112500">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.7.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Isis&#8217; Obligations</u></font><font style="font-size: 10pt;">. Isis will promptly, accurately and completely list, with the applicable Regulatory Authorities
                    during the Agreement Term, all applicable Patent Rights that Cover a Discontinued Product. Prior to such listings, the Parties will meet, through the Joint Patent Committee, to evaluate and identify all applicable Patent Rights, and
                    Isis will have the right to review, where reasonable, original records relating to any invention for which Patent Rights are being considered by the Joint Patent Committee for any such listing. Notwithstanding the preceding sentence,
                    Isis will retain final decision-making authority as to the listing of all applicable Patent Rights for such Discontinued Products, as applicable, regardless of which Party owns such Patent Rights.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z18b7e25d4ca44bc0b8d20cc3b945e439">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.8.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>CREATE Act</u></font><font style="font-size: 10pt;">. Notwithstanding anything to the contrary in this <u>ARTICLE 7</u>, neither Party will have the right
                    to make an election under the CREATE Act when exercising its rights under this <u>ARTICLE 7</u> without the prior written consent of the other Party, which will not be unreasonably withheld, conditioned or delayed. With respect to any
                    such permitted election, the Parties will use reasonable efforts to cooperate and coordinate their activities with respect to any submissions, filings or other activities in support thereof. The Parties acknowledge and agree that this
                    Agreement is a &#8220;<font style="font-style: italic;">joint research agreement</font>&#8221; as defined in the CREATE Act.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zbf2ba678188a473da0a094b51880f33c">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.9.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Obligations to Third Parties</u></font><font style="font-size: 10pt;">. Notwithstanding any of the foregoing, each Party&#8217;s rights and obligations with
                    respect to Licensed Technology under this ARTICLE 7 will be subject to the Third Party rights and obligations under any (i) Third Party agreements the restrictions and obligations of which Roche has agreed to under <u>Section 6.11.2(b)</u>,
                    (ii) Prior Agreements, and (iii) Isis In-License Agreements; <font style="font-style: italic;">provided, however</font>, that, to the extent that Isis has a non-transferable right to prosecute, maintain or enforce any Patent Rights
                    licensed to Roche hereunder and, this Agreement purports to grant any such rights to Roche, Isis will act in such regard with respect to such Patent Rights at Roche&#8217;s direction.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z3a5b81eb23c9407b83b060f3f3db244a">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.10.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Additional Right and Exceptions</u></font><font style="font-size: 10pt;">. Notwithstanding any provision of this <u>ARTICLE 7</u>, but subject
                    to <u>Section 7.4.3</u>,&#160; Isis retains the sole right to Prosecute and Maintain Isis Core Technology Patents and Isis Manufacturing and Analytical Patents during the Agreement Term and to control any enforcement of Isis Core Technology
                    Patents and Isis Manufacturing and Analytical Patents, and will take the lead on such enforcement solely to the extent that the scope or validity of any Patent Rights Controlled by Isis and Covering the Isis Core Technology Patents or
                    Isis Manufacturing and Analytical Patents is at risk. If Isis determines, in Isis&#8217; sole discretion, to not enforce any Isis Core Technology Patents or Isis Manufacturing and Analytical Patents and does not permit Roche to so enforce
                    such Patent Rights, then the Parties will mutually agree on an appropriate adjustment (if any) of the future consideration payable by Roche under this Agreement to reflect any adverse impact Isis&#8217; failure to enforce such Patent Rights
                    has on Products.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z67eeeba072ac40b8bb2715753274341e">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.11.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Patent Term Extension</u></font><font style="font-size: 10pt;">.<font style="font-weight: bold;">&#160;</font>The Parties will cooperate with each other in
                    gaining patent term extension wherever applicable to a Product, including European supplementary protection certificates and pediatric exclusivity. After exercising the Option, Roche will determine which patents will be extended and
                    what extensions will be sought.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">45</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z3d9980ecffb843dd90bd24e224f3280b">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">7.12.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>No Challenge</u></font><font style="font-size: 10pt;">. If, during the Agreement Term, solely with respect to rights to the Licensed Patents that are
                    included (or, prior to Option exercise, are eligible to be included) in a license granted to Roche under <u>Section 4.1.1</u>, Roche, its Affiliates or Sublicensees, in the United States or any other country, (a) commence or otherwise
                    voluntarily determine to participate in (other than as may be necessary or reasonably required to assert a cross-claim or a counter-claim or to respond to a court request or order or administrative law request or order) any action or
                    proceeding, challenging or denying the enforceability or validity of any claim within an issued patent or patent application within such Licensed Patents, or (b) direct, support or actively assist any other Person (other than as may be
                    necessary or reasonably required to assert a cross-claim or a counter-claim or to respond to a court request or order or administrative law request or order) in bringing or prosecuting any action or proceeding challenging or denying the
                    validity of any claim within an issued patent or patent application within such Licensed Patents, then unless, within thirty (30) days after written notice from Isis, Roche rescinds any actions brought by Roche, its Affiliates, or
                    Sublicensees, Isis may terminate this Agreement and the provisions of <u>Section 10.4.1</u> and <u>Section 10.4.2</u> will apply; [<font style="color: rgb(0, 0, 0);">***</font>].</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="text-align: center; font-weight: bold;">ARTICLE 8.</div>
        <div style="text-align: center; font-weight: bold;">REPRESENTATIONS AND WARRANTIES</div>
        <div>&#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="z61fdc09cac2f44e794e4843273d0400e">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Representations and Warranties of Both Parties</u></font><font style="font-size: 10pt;">. Each Party hereby represents and warrants to the other Party, as of
                    the Effective Date, that:</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z5429c7d49f314be2834ee2d5ac07e55c">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.1.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>such Party is duly organized, validly existing and in good standing under the laws of the jurisdiction of its incorporation or organization and has full corporate power and authority to enter into this Agreement and to carry out the
                  provisions hereof;</div>
              </td>
            </tr>

        </table>
        <div>&#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="ze953129196d94bfdb04094687245d705">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.1.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>such Party has taken all necessary action on its part to authorize the execution and delivery of this Agreement and the performance of its obligations hereunder;</div>
              </td>
            </tr>

        </table>
        <div>&#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="zfed48b8e17cb46be9fcb3a3265e9a345">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.1.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>this Agreement has been duly executed and delivered on behalf of such Party, and constitutes a legal, valid and binding obligation, enforceable against it in accordance with the terms hereof;</div>
              </td>
            </tr>

        </table>
        <div>&#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="z3c5723347ebd4fdcb479cb4ffc2ff10b">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.1.4.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>the execution, delivery and performance of this Agreement by such Party will not constitute a default under or conflict with any agreement, instrument or understanding, oral or written, to which it is a party or by which it is bound,
                  or to the best of its knowledge and belief violate any law or regulation of any court, governmental body or administrative or other agency having jurisdiction over such Party;</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">46</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z801c5f78f56c40e682f2898a39905e2d">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.1.5.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>to the best of its knowledge and belief, no government authorization, consent, approval, license, exemption of or filing or registration with any court or governmental department, commission, board, bureau, agency or instrumentality,
                  domestic or foreign, under any applicable laws, rules or regulations currently in effect, is or will be necessary for, or in connection with, the transaction contemplated by this Agreement or any other agreement or instrument executed in
                  connection herewith, or for the performance by it of its obligations under this Agreement and such other agreements; and</div>
              </td>
            </tr>

        </table>
        <div>&#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="ze6e349091c004231a8c6268745193563">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.1.6.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>it has not employed (and, to the best of its knowledge and belief, has not used a contractor or consultant that has employed) and in the future will not employ (or, to the best of its knowledge, use any contractor or consultant that
                  employs, provided that such Party may reasonably rely on a representation made by such contractor or consultant) any Person debarred by the FDA (or subject to a similar sanction of EMA or foreign equivalent), or any Person which is the
                  subject of an FDA debarment investigation or proceeding (or similar proceeding of EMA or foreign equivalent), in the conduct of the Pre-Clinical Studies or Clinical Studies of a Product and its activities under the R&amp;D Plans.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z863a4501e25b47189491e68fec40d8d4">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Representations and Warranties of Isis</u></font><font style="font-size: 10pt;">. Isis hereby represents and warrants to Roche, as of the Effective Date,
                    that:</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z909706b0dd8a4834a8240a3e6852f4ca">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.2.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>To the best of its knowledge and belief, there are no additional licenses (beyond those that would be granted to Roche under <u>Section 4.1.1</u> upon the exercise of the Option for a Product arising under the Isis Development
                  Candidate-R&amp;D Plan) under any intellectual property owned or Controlled by Isis or its Affiliates as of the Effective Date that would be required in order for Roche to further Develop and Commercialize a Product arising under the Isis
                  Development Candidate-R&amp;D Plan existing on the Effective Date.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z17484eff635b4bbaafe3714bef8a03f1">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.2.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>The Licensed Technology existing as of the Effective Date constitutes all of the Patent Rights and Know-How Controlled by Isis as of the Effective Date that are necessary to Develop, Manufacture or Commercialize Compounds contemplated
                  under the Isis Development Candidate-R&amp;D Plan existing on the Effective Date in the Field.&#160; Isis has not previously assigned, transferred, conveyed or otherwise encumbered its right, title and interest in the Licensed Technology in a
                  manner that conflicts with any rights granted to Roche hereunder.</div>
              </td>
            </tr>

        </table>
        <div>&#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="zc67281541a2d4fc98b37e7ca0ee2471d">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.2.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>There are no claims, judgments or settlements against or owed by Isis or its Affiliates or pending against Isis or, to the best of Isis&#8217; knowledge, threatened against Isis, in each case relating to the Isis Technology that could impact
                  activities under this Agreement. To the best of Isis&#8217; knowledge, there are no claims, judgments or settlements against or owed by any Third Party that is party to a Prior Agreement, or pending or threatened claims or litigation against
                  any Third Party that is party to a Prior Agreement, in each case relating to the Isis Technology that would impact activities under this Agreement.</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">47</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z39ee3a25c5024243bc66a7ce2bd0c5cf">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.2.4.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><u><font style="font-size: 10pt; font-variant: small-caps;">Schedule</font><font style="font-size: 10pt;">&#160;8.2.4(a)</font></u><font style="font-size: 10pt;">, <u><font style="font-variant: small-caps;">Schedule</font>&#160;8.2.4(b)</u>
                    and <u><font style="font-variant: small-caps;">Schedule</font>&#160;8.2.4(c)</u> set forth true, correct and complete lists of all Isis Core Technology Patents, Isis Manufacturing and Analytical Patents, and Isis Product-Specific Patents
                    that apply to the Compounds contemplated under the Isis Development Candidate-R&amp;D Plan as of the Effective Date, respectively, and indicates whether each such Patent Right is owned by Isis or licensed by Isis from a Third Party and
                    if so, identifies the licensor or sublicensor from which the Patent Right is licensed.&#160; Isis Controls such Patent Rights existing as of the Effective Date and is entitled to grant all rights and licenses (or sublicenses, as the case may
                    be) under such Patent Rights it purports to grant to Roche under this Agreement.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z7fd920a8a41442309bd7b7ffba683814">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.2.5.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>(a) There is no fact or circumstance known by Isis that would cause Isis to reasonably conclude that any Licensed Patent is invalid or un-enforceable, (b) there is no fact or circumstance known by Isis that would cause Isis to
                  reasonably conclude the inventorship of each Licensed Patent is not properly identified on each patent, (c) all official fees, maintenance fees and annuities for the Licensed Patents have been paid and all administrative procedures with
                  governmental agencies have been completed, (d) none of the Isis Product-Specific Patents that would be licensed by Isis to Roche upon Option exercise under this Agreement are currently involved in any interference, reissue,
                  re-examination, cancellation or opposition proceeding and neither Isis, nor any of its Affiliates, has received any written notice from any person, or has knowledge, of such actual or threatened proceeding, and (e) to the best of Isis&#8217;
                  knowledge and belief, Roche&#8217;s practice of the inventions claimed in the Isis Product-Specific Patents in the performance of the Roche R&amp;D Activities contemplated as of the Effective Date will not [***].</div>
              </td>
            </tr>

        </table>
        <div>&#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="z2962873e4c5548b086287a7a4d4c1543">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.2.6.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><u><font style="font-size: 10pt; font-variant: small-caps;">Schedule</font><font style="font-size: 10pt;">&#160;6.11.1</font></u><font style="font-size: 10pt;"> sets forth true, correct and complete lists of all
                    Isis In-License Agreements relating to Licensed Technology necessary or useful to conduct the research, Development, Manufacture or Commercialization of Compounds as contemplated under the Isis Development Candidate-R&amp;D Plan
                    existing on the Effective Date. All Isis In-License Agreements are in full force and effect and have not been modified or amended. Neither Isis nor, to the best knowledge of Isis, the Third Party licensor in an Isis In-License Agreement
                    is in default with respect to a material obligation under such Isis In-License Agreement, and neither such party has claimed or has grounds upon which to claim that the other party is in default with respect to a material obligation
                    under, any Isis In-License Agreement.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z6a196140cab64830a2bb3e93ea47ada5">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.2.7.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><u><font style="font-size: 10pt; font-variant: small-caps;">Schedule</font><font style="font-size: 10pt;">&#160;8.2.7</font></u><font style="font-size: 10pt;"> is a complete and accurate list of all agreements that
                    create Third Party Obligations that affect the rights granted by Isis to Roche under this Agreement with respect to Isis Development Candidates contemplated by the R&amp;D Plans on the Effective Date.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z0d520a56e4ad4affa7bc2eb5bbfa61ef">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.2.8.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Isis has all rights necessary to grant the option and licenses contained in this Agreement, and has the ability to work exclusively with Roche as set forth in this Agreement, including the covenants granted in <u>Section 2.1</u>.</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">48</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z043415f9b0bf403ea49d826320f680bd">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Isis Covenants</u></font><font style="font-size: 10pt;">. Isis hereby covenants to Roche that, except as expressly permitted under this Agreement:</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zb4b61baab1e34216ad139522429837e6">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.3.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Isis will promptly amend <u><font style="font-variant: small-caps;">Schedule</font>&#160;8.2.4(a)</u>, <u><font style="font-variant: small-caps;">Schedule</font>&#160;8.2.4(b)</u> and <u><font style="font-variant: small-caps;">Schedule</font>&#160;8.2.4(c)</u><font style="color: rgb(0, 0, 0);"> and submit such amended </font>Schedules to Roche if Isis <font style="color: rgb(0, 0, 0);">becomes aware that any </font>Isis Core Technology Patents<font style="color: rgb(0, 0, 0);">, </font>Isis
                  Manufacturing <font style="color: rgb(0, 0, 0);">and Analytical Patents or </font>Isis Product-Specific Patents <font style="color: rgb(0, 0, 0);">are not properly identified on such Schedule.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z85e51bea01cb49958b3d891f24fd77d9">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.3.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>during the Agreement Term, Isis will maintain and not breach any Isis In-License Agreements and any agreements with Third Parties entered into after the Effective Date (&#8220;<font style="font-weight: bold; font-style: italic;">New Third
                    Party Licenses</font>&#8221;) that provide a grant of rights from such Third Party to Isis that are Controlled by Isis and are licensed or may become subject to a license from Isis to Roche for a Product under this Agreement;</div>
              </td>
            </tr>

        </table>
        <div>&#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="zec4af625d6aa4e749ab29b518b5db479">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.3.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Isis will promptly notify Roche of any material breach by Isis or a Third Party of any New Third Party License, and in the event of a breach by Isis, will permit Roche to cure such breach on Isis&#8217; behalf upon Roche&#8217;s request;</div>
              </td>
            </tr>

        </table>
        <div>&#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="z7d1cf5d3464c4d9bb0a7386b9fb33662">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.3.4.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Isis will not amend, modify or terminate any Isis In-License Agreement or New Third Party License in a manner that would adversely affect Roche&#8217;s rights hereunder without first obtaining Roche&#8217;s written consent, which consent may be
                  withheld in Roche&#8217;s sole discretion;</div>
              </td>
            </tr>

        </table>
        <div>&#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="za363511fddd84e24a4e995704bb86bd9">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.3.5.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Isis will not enter into any new agreement or other obligation with any Third Party, or amend an existing agreement with a Third Party, in each case that restricts, limits or encumbers the rights granted to Roche under this Agreement;</div>
              </td>
            </tr>

        </table>
        <div>&#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="z32c48c659dec44ad8076b139fe1e072b">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.3.6.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Isis will cause its Affiliates, licensees and sublicensees to comply with the terms of <u>Section 2.1</u>;</div>
              </td>
            </tr>

        </table>
        <div>&#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="z0b71f51cead1433ea5dcdd12be17f3f0">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.3.7.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>all employees and contractors of Isis performing Development activities hereunder on behalf of Isis will be obligated to assign all right, title and interest in and to any inventions (or grant a license to Isis or an option to obtain
                  such a license) developed by them, whether or not patentable, to Isis or such Affiliate, respectively, as the sole owner thereof; and</div>
              </td>
            </tr>

        </table>
        <div>&#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="z959b24fcaafe4c73994f889d92256d0b">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.3.8.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>If, after the Effective Date, Isis becomes the owner or otherwise acquires Control of any formulation or delivery technology that would be necessary or useful in order for Roche to further Develop, Manufacture or Commercialize a
                  Product, and Roche has exercised its Option and the license granted to Roche under this Agreement is in effect, Isis will make such technology available to Roche on commercially reasonable terms.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z619dffe5c029416d9aba00b1a526e597">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.4.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Representations and Warranties of Roche</u></font><font style="font-size: 10pt;">. Roche hereby represents and warrants to Isis, as of the Effective Date,
                    that:</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">49</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="zf57fa0c4984545aea0a9d88d61a378d2">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.4.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><u><font style="font-size: 10pt; font-variant: small-caps;">Schedule 8.4.1</font></u><font style="font-size: 10pt;"> sets forth a true and correct list of Patent Rights owned or Controlled as of the Effective
                    Date by Roche or its Affiliates that (i) specifically claim Roche&#8217;s Brain Shuttle technology, or (ii) are necessary or useful for the research, Development or Commercialization of a Brain Shuttle Development Candidate (such Patent
                    Rights, &#8220;<font style="font-weight: bold; font-style: italic;">Roche Existing Brain Shuttle Patents</font>&#8221;).&#160; Roche Controls such Roche Existing Brain Shuttle Patents existing as of the Effective Date and is entitled to grant all rights
                    and licenses (or sublicenses, as the case may be) under such Roche Existing Brain Shuttle Patents it purports to grant to Isis under this Agreement; and</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zff62af10ed6c4a44b04bff7508dbe655">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.4.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>(a) There is no fact or circumstance known by Roche that would cause Roche to reasonably conclude that any Roche Existing Brain Shuttle Patent is invalid or un-enforceable, (b) there is no fact or circumstance known by Roche that would
                  cause Roche to reasonably conclude the inventorship of each Roche Existing Brain Shuttle Patent is not properly identified on each patent, (c) all official fees, maintenance fees and annuities for the Roche Existing Brain Shuttle Patents
                  have been paid and all administrative procedures with governmental agencies have been completed, (d) none of the Roche Existing Brain Shuttle Patent are currently involved in any interference, reissue, re-examination, cancellation or
                  opposition proceeding and neither Isis, nor any of its Affiliates, has received any written notice from any person, or has knowledge, of such actual or threatened proceeding, and (e) to the best of Roche&#8217;s knowledge and belief, Isis&#8217;
                  practice of the inventions claimed in the Roche Existing Brain Shuttle Patents in the performance of the Isis R&amp;D Activities contemplated as of the Effective Date will not infringe the Patent Rights of any Third Party.</div>
              </td>
            </tr>

        </table>
        <div>&#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="zff1fe048043b434e968d9e251f12e82a">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">8.5.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>DISCLAIMER</u>.</font><font style="font-size: 10pt;">&#160;<font style="font-weight: bold;">EXCEPT AS OTHERWISE EXPRESSLY SET FORTH IN THIS AGREEMENT, NEITHER
                      PARTY NOR ITS AFFILIATES MAKES ANY REPRESENTATION OR EXTENDS ANY WARRANTY OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING ANY WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. ROCHE AND ISIS UNDERSTAND THAT PRODUCTS
                      ARE THE SUBJECT OF ONGOING RESEARCH AND DEVELOPMENT AND THAT NEITHER PARTY CAN ASSURE THE SAFETY, USEFULNESS OR COMMERCIAL OR TECHNICAL VIABILITY OF THE PRODUCTS.</font></font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="text-align: center; font-weight: bold;">ARTICLE 9.</div>
        <div style="text-align: center; font-weight: bold;">INDEMNIFICATION; INSURANCE</div>
        <div>&#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="zbe8cc6c81a634487b84a3e62eccc9180">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">9.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Indemnification by Roche</u></font><font style="font-size: 10pt;">. Roche will indemnify, defend and hold harmless Isis and its Affiliates, and its or their
                    respective directors, officers, employees and agents, from and against any and all liabilities, damages, losses, costs and expenses including the reasonable fees of attorneys (collectively &#8220;<font style="font-weight: bold; font-style: italic;">Losses</font>&#8221;) arising out of or resulting from any and all Third Party suits, claims, actions, proceedings or demands (&#8220;<font style="font-weight: bold; font-style: italic;">Claims</font>&#8221;) based upon:</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">50</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z4ad92890d2ad484a8870c83e12ad4b60">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">9.1.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>the gross negligence or willful misconduct of Roche, its Affiliates <font style="color: rgb(0, 0, 0);">or</font> Sublicensees and its or their respective directors, officers, employees and agents, in connection with Roche&#8217;s
                  performance of its obligations or exercise of its rights under this Agreement;</div>
              </td>
            </tr>

        </table>
        <div>&#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="z63fec3f590764d5d8b08512e839f800e">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">9.1.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>any breach of any representation or warranty or express covenant made by Roche under <u>ARTICLE 8</u> or any other provision under this Agreement;</div>
              </td>
            </tr>

        </table>
        <div>&#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="z04a16202c0594c108d8fe94c7c460a4e">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">9.1.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>the Development or Manufacturing activities that are conducted by <font style="color: rgb(0, 0, 0);">or</font> on behalf of Roche or its Affiliates or Sublicensees (which will exclude any Development or Manufacturing activities that
                  are conducted by <font style="color: rgb(0, 0, 0);">or</font> on behalf of Isis pursuant to this Agreement); or</div>
              </td>
            </tr>

        </table>
        <div>&#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="ze2bdaf4dbc0b4d3c907b990ad7cfec94">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">9.1.4.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>the Commercialization of a Product by or on behalf of Roche or its Affiliates or Sublicensees;</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="text-align: justify; margin-left: 36pt; font-size: 12pt;"><font style="font-size: 10pt; font-style: italic;"><u>except</u></font><font style="font-size: 10pt;">, in each case above, to the extent such Claim arose out of or resulted from
            or is attributable to any acts or omissions of Isis <font style="color: rgb(0, 0, 0);">or</font> its Affiliates, licensees, Sublicensees or contractors, and its or their respective directors, officers, employees and agents or other
            circumstance for which Isis has an indemnity obligation pursuant to <u>Section 9.2</u>.</font></div>
        <div>&#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="z233a722d9dce401e9b768c71b855f504">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">9.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Indemnification by Isis</u></font><font style="font-size: 10pt;">. Isis will indemnify, defend and hold harmless Roche and its Affiliates, and its or their
                    respective directors, officers, employees and agents, from and against any and all Losses arising out of or resulting from any and all Claims based upon:</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z91621dfeb8644f3894b562017f5c36b9">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">9.2.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>the gross negligence or willful misconduct of Isis, its Affiliates <font style="color: rgb(0, 0, 0);">or</font> Sublicensees <font style="color: rgb(0, 0, 0);">or</font> its or their respective directors, officers, employees and
                  agents, in connection with Isis&#8217; performance of its obligations or exercise of its rights under this Agreement;</div>
              </td>
            </tr>

        </table>
        <div>&#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="z08558c5b9a84400686fe8dfdd84e5264">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">9.2.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>any breach of any representation or warranty or express covenant made by Isis under <u>ARTICLE 8</u> or any other provision under this Agreement;</div>
              </td>
            </tr>

        </table>
        <div>&#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="z3a52528bc1164174a075381160bc5e21">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">9.2.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>any Development or Manufacturing activities that are conducted by <font style="color: rgb(0, 0, 0);">or</font> on behalf of Isis or its Affiliates or Sublicensees (which will exclude any Development or Manufacturing activities that
                  are conducted by <font style="color: rgb(0, 0, 0);">or</font> on behalf of Roche pursuant to this Agreement); or</div>
              </td>
            </tr>

        </table>
        <div>&#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="z8df98738aa5f420eb339fccd552c5642">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">9.2.4.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>any development, manufacturing or commercialization activities that are conducted by <font style="color: rgb(0, 0, 0);">or</font> on behalf of Isis or its Affiliates or Sublicensees with respect to a Discontinued Product.</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="text-align: justify; margin-left: 36pt; font-size: 12pt;"><font style="font-size: 10pt; font-style: italic;"><u>except</u></font><font style="font-size: 10pt;">, in each case above, to the extent such Claim arose out of or resulted from
            or is attributable to any acts or omissions of Roche <font style="color: rgb(0, 0, 0);">or</font> its Affiliates, licensees, Sublicensees or contractors and its or their respective directors, officers, employees and agents or other
            circumstance for which Roche has an indemnity obligation pursuant to <u>Section 9.1</u>.</font></div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">51</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z8eca98ac9f8f4c78a3ecf23497b08631">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">9.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Procedure</u></font><font style="font-size: 10pt;">. If a Person entitled to indemnification under <u>Section 9.1</u> or <u>Section 9.2</u> (an &#8220;<font style="font-weight: bold; font-style: italic;">Indemnitee</font>&#8221;) seeks such indemnification, such Indemnitee will (i) inform the indemnifying Party in writing of a Claim as soon as reasonably practicable after such Indemnitee
                    receives notice of such Claim, (ii) permit the indemnifying Party to assume direction and control of the defense of the Claim (including the sole right to settle such Claim at the sole discretion of the indemnifying Party, <font style="font-style: italic;">provided that</font> such settlement or compromise does not admit any fault or negligence on the part of the Indemnitee, or impose any obligation on, or otherwise materially adversely affect, the Indemnitee
                    or other Party), (iii) cooperate as reasonably requested (at the expense of the indemnifying Party) in the defense of the Claim, and (iv) undertake reasonable steps to mitigate any Losses with respect to the Claim. The provisions of <u>Section
                       7.4</u> will govern the procedures for responding to a Claim of infringement described therein. Notwithstanding anything in this Agreement to the contrary, the indemnifying Party will have no liability under <u>Section
                      9.1</u> or <u>Section 9.2</u>, as the case may be, for Claims settled or compromised by the Indemnitee without the indemnifying Party&#8217;s prior written consent.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z27e17c30bd36495dacd150154cbf5c8e">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">9.4.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Insurance</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div><br>
        </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="zebf97c825f0544478e4eb8d04f617ace">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">9.4.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Isis&#8217; Insurance Obligations</u></font><font style="font-size: 10pt;">. Isis will maintain, at its cost, reasonable insurance against liability and other
                    risks associated with its activities contemplated by this Agreement, including but not limited to its indemnification obligations herein, in such amounts and on such terms as are customary for prudent practices for biotech companies of
                    similar size and with similar resources in the pharmaceutical industry for the activities to be conducted by it under this Agreement taking into account the scope of development of products. Isis will furnish to Roche evidence of any
                    insurance required under this <u>Section 9.4.1</u>, upon request.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="za8d3782d5f0d49df9d8c967c796557c0">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">9.4.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Roche&#8217;s Insurance Obligations</u></font><font style="font-size: 10pt;">. Roche hereby represents and warrants to Isis that it will maintain, at its cost,
                    reasonable insurance or self insure against liability and other risks associated with its activities contemplated by this Agreement (including product liability), including but not limited to its indemnification obligations herein, in
                    such amounts and on such terms as are customary for prudent practices for large companies in the pharmaceutical industry for the activities to be conducted by Roche under this Agreement. Roche will maintain such self insurance
                    throughout the Agreement Term and for five years thereafter, and will furnish to Isis evidence of such insurance, upon request.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z4b7e37b6b5a44901ab2eafa6a1a517bb">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">9.5.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>LIMITATION OF CONSEQUENTIAL DAMAGES</u></font><font style="font-size: 10pt;">. <font style="font-weight: bold;">EXCEPT FOR (a) CLAIMS OF A THIRD PARTY THAT
                      ARE SUBJECT TO INDEMNIFICATION UNDER THIS <u>ARTICLE 9</u></font>,<font style="font-weight: bold;"> (b) CLAIMS ARISING OUT OF A PARTY&#8217;S WILLFUL MISCONDUCT OF THIS AGREEMENT, (c) A PARTY&#8217;S BREACH OF <u>ARTICLE 2</u>,
                      OR A BREACH OF <u>SECTION 10.4.1(b)</u> BY ROCHE OR ITS AFFILIATES 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, 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.</font></font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">52</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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;">ARTICLE 10.</div>
        <div style="text-align: center; font-weight: bold;">TERM; TERMINATION</div>
        <div>&#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="z741e04d819f74a62af5caf852ca94b9b">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">10.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Agreement Term; Expiration</u></font><font style="font-size: 10pt;">. This Agreement is effective as of the Effective Date and, unless earlier terminated
                    pursuant to the other provisions of this <u>ARTICLE 10</u>, will continue in full force and effect until this Agreement expires as follows:</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z303d509c8ef641c38e4f096f9df4eaae">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">10.1.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>on a country-by-country basis, on the date of expiration of all payment obligations by the Commercializing Party under this Agreement with respect to a Product (or a Discontinued Product) in such country;</div>
              </td>
            </tr>

        </table>
        <div>&#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="z2a037fd10e09477595e564a6b396aaba">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">10.1.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>in its entirety upon the expiration of all payment obligations under this Agreement with respect to the last Product (or last Discontinued Product) in all countries pursuant to <u>Section 10.1.1</u>; and</div>
              </td>
            </tr>

        </table>
        <div>&#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="z9db98ebc890a4cb3a7106d57bba833be">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">10.1.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>where Roche has not provided Isis a written notice stating Roche is exercising its Option under <u>Section 6.3</u> by the Option Deadline.</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="text-align: justify; margin-left: 36pt;">The period from the Effective Date until the date of expiration of this Agreement pursuant to this <u>Section 10.1</u> is the &#8220;<font style="font-weight: bold; font-style: italic;">Agreement Term</font>.&#8221;



          On a Product-by-Product basis, if with respect to a particular Product this Agreement expires (<u>i.e.</u>, is not terminated early) under <u>Section 10.1.1</u> or <u>Section 10.1.2</u> in a particular country, then, effective upon such
          expiration, Isis will and hereby does grant to Roche a fully paid-up and irrevocable non-exclusive license under the Licensed Technology to Manufacture, Develop and Commercialize the Product that is the subject of such expiration in such country.</div>
        <div>&#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="z881de8a6c0b549e9bd4e576cd35fcf1d">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">10.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Termination of the Agreement</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zab18ef6f7e9d40f4b950ec9862593006">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">10.2.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Roche&#8217;s Termination for Convenience</u></font><font style="font-size: 10pt;">.<font style="font-weight: bold;">&#160;</font>After payment by Roche of the upfront
                    fee under <u>Section 6.1</u>, subject to <u>Section 10.4.1</u> below, Roche may terminate this Agreement for convenience by providing ninety (90) days written notice to Isis of such termination. If Roche terminates this Agreement for
                    convenience under this <u>Section 10.2.1</u> prior to Roche paying Isis the milestone payment for achievement of the Initiation of a Phase 1 Trial Milestone Event, then if (i) Isis continues to develop the Product after such
                    termination and achieves the Initiation of the Phase 1 Trial Milestone Event for such Product, and (ii) Isis has not granted a Third Party an exclusive license or an exclusive option to obtain an exclusive license to such Product by the
                    [***], then [***], unless by that time Isis has undergone or has agreed to a Change of Control, in which case no such payment shall be due or payable. &#160; </font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">53</font></div>
          <div class="BRPFPageBreak" style="page-break-after: always;">
            <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" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z16542d82546c488cb8e75661329c4b68">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">10.2.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Termination for Material Breach</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z47113f0c85cf4e1e8f54eed21db00336">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Roche&#8217;s Right to Terminate</u></font><font style="font-size: 10pt;">. If Roche believes that Isis is in material breach of this Agreement (other than with
                    respect to a failure to use Commercially Reasonable Efforts under <u>ARTICLE 1</u>, which is governed by <u>Section 10.2.3</u> below), then Roche may deliver notice of such material breach to Isis. If the breach is curable, Isis will
                    have sixty (60) days to cure such breach. If Isis fails to cure such breach within the sixty (60) day period, or if the breach is not subject to cure, Roche may terminate this Agreement by providing written notice to Isis.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z532453eb3cae4429b1d01d2f43413af8">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Isis&#8217; Right to Terminate</u></font><font style="font-size: 10pt;">. If Isis believes that Roche is in material breach of this Agreement (other than with
                    respect to a failure to use Commercially Reasonable Efforts under <u>ARTICLE 1</u> or <u>Section 5.1</u>, which is governed by <u>Section 10.2.3</u> below), then Isis may deliver notice of such material breach to Roche. If the breach
                    is curable, Roche will have sixty (60) days to cure such breach (except to the extent such breach involves the failure to make a payment when due, which breach must be cured within thirty (30) days following such notice). If Roche fails
                    to cure such breach within the sixty (60) day or thirty (30) day period, as applicable, or if the breach is not subject to cure, Isis may terminate this Agreement by providing written notice to Roche.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z3593e7d21bc14ec188400645d03f53bc">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">10.2.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Remedies for Failure to Use Commercially Reasonable Efforts</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zc9d5974f502d47fca45d58ae8b919bda">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>If Isis, in Roche&#8217;s reasonable determination, fails to use Commercially Reasonable Efforts in the activities contemplated in <u>ARTICLE 1</u> prior to Option exercise, Roche will notify Isis and, within thirty (30) days thereafter,
                  Isis and Roche will 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 related to Isis&#8217; use of Commercially Reasonable Efforts in <u>ARTICLE
                      1</u>. Following such a meeting, if Isis fails to use Commercially Reasonable Efforts as contemplated by <u>ARTICLE 1</u>, then subject to <u>Section 10.2.4</u> below, Roche will have the right, at its sole discretion, to (i)
                  terminate this Agreement, or (ii) prior to Option exercise, Roche may elect to trigger the alternative remedy provisions of <u>Section 10.3</u> below in lieu of terminating this Agreement by providing written notice to Isis. If Roche
                  elects to trigger the alternative remedy provisions of <u>Section 10.3</u> below, then such election is Roche&#8217;s sole and exclusive remedy if Isis fails to use Commercially Reasonable Efforts in the activities contemplated in <u>ARTICLE
                    1</u> prior to Option exercise.&#160; </div>
              </td>
            </tr>

        </table>
        <div>&#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="z4c6a453acd4f462b88fb43762e308b37">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>If Roche, in Isis&#8217; reasonable determination, fails to use Commercially Reasonable Efforts under <u>ARTICLE 1</u> or <u>Section 5.1</u> above, Isis will notify Roche and, within thirty (30) days thereafter, Isis and Roche will 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 related to Roche&#8217;s use of Commercially Reasonable Efforts in <u>ARTICLE 1</u> or <u>Section
                    5.1</u>. Following such a meeting, if Roche fails to use Commercially Reasonable Efforts as contemplated by <u>ARTICLE 1</u> or <u>Section 5.1</u>, then subject to <u>Section 10.2.4</u> below, Isis will have the right,
                  at its sole discretion, to terminate this Agreement.</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">54</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="zbbb9922c72e845a79701e69ccce4bacb">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">10.2.4.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Disputes Regarding Material Breach</u></font><font style="font-size: 10pt;">. Notwithstanding the foregoing, if the Breaching Party in <u>Section 10.2.2</u>
                    or <u>Section 10.2.3</u> disputes in good faith the existence, materiality, or failure to cure of any such breach which is not a payment breach, and provides notice to the Non-Breaching Party of such dispute within such sixty (60) day
                    period, the Non-Breaching Party will not have the right to terminate this Agreement in accordance with <u>Section 10.2.2</u> or <u>Section </u><u>10.2.3</u>, or trigger the alternative remedy provisions of <u>Section 10.3</u>, as
                    applicable, unless and until it has been determined in accordance with <u>Section 12.1</u> that this Agreement was materially breached by the Breaching Party and the Breaching Party fails to cure such breach within thirty (30) days
                    following such determination. It is understood and acknowledged that during the pendency of such dispute, all the terms 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.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z5752e6979a3b42399449e2b2ddac8faa">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">10.2.5.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Termination for Insolvency</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z3c4b247226e1407cb091350707cc28b6">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Either Party may terminate this Agreement if, at any time, the other Party files in any court or agency pursuant to any statute or regulation of any state or country a petition in bankruptcy or insolvency or for reorganization or for
                  an arrangement or for the appointment of a receiver or trustee of the Party or of substantially all of its assets; or if the other Party proposes a written agreement of composition or extension of substantially all of its debts; or if the
                  other Party will be served with an involuntary petition against it, filed in any insolvency proceeding, and such petition will not be dismissed within ninety (90) days after the filing thereof; or if the other Party will propose or be a
                  party to any dissolution or liquidation; or if the other Party will make an assignment of substantially all of its assets for the benefit of creditors.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z54a48020fe5d487e9ccdfaeb35ff8e36">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>All rights and licenses granted under or pursuant to any section of this Agreement are and will otherwise be deemed to be for purposes of Section 365(n) of Title 11, United States Code (the &#8220;<font style="font-weight: bold; font-style: italic;">Bankruptcy Code</font>&#8221;) licenses of rights to &#8220;intellectual property&#8221; as defined in Section 101(56) of the Bankruptcy Code. The Parties will retain and may fully exercise all of their respective rights and elections under the
                  Bankruptcy Code.&#160; Upon the bankruptcy of any Party, the non-bankrupt Party will further be entitled to a complete duplicate of, or complete access to, any such intellectual property, and such, if not already in its possession, will be
                  promptly delivered to the non-bankrupt Party, unless the bankrupt Party elects in writing to continue, and continues, to perform all of its obligations under this Agreement.</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">55</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z30bc4523444b4176ad883060f1e72979">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">10.2.6.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Termination if Development Candidate Not Identified</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z4e82fc9c558942f48586f0464f9c31f0">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Failure to Identify a Brain Shuttle Development Candidate</u></font><font style="font-size: 10pt;">. If, despite the Parties&#8217;
                    Commercially Reasonable Efforts, Roche has not designated at least one Brain Shuttle Development Candidate by the [***] of the Effective Date, then either Party will have the right to terminate this Agreement solely with respect to the
                    Brain Shuttle Development Candidate-R&amp;D Plan by providing written notice to the other Party within [***] of the Effective Date. In the case of termination of this Agreement under this <u>Section 10.2.6(a)</u>, <u>Section 10.4.1</u>
                    will apply solely with respect to the Brain Shuttle Development Candidate-R&amp;D Plan. Nothing in this <u>Section 10.2.6(a)</u> will terminate or otherwise affect the provisions of this Agreement with respect to the Isis Development
                    Candidate-R&amp;D Plan, which shall remain in full force and effect.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="za99e68506c1e42148c94542e1bff17df">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Failure to Identify an Isis Development Candidate</u></font><font style="font-size: 10pt;">. If, despite Isis&#8217; Commercially Reasonable
                    Efforts, Isis has not designated at least one Isis Development Candidate by the [***] of the Effective Date, then either Party will have the right to terminate this Agreement with respect to the Isis Development Candidate-R&amp;D Plan
                    by providing written notice to the other Party within [***] of the Effective Date. In the case of termination of this Agreement under this <u>Section 10.2.6(b)</u>, <u>Section 10.4.1</u> will apply solely with respect to the Isis
                    Development Candidate-R&amp;D Plan.&#160; Nothing in this <u>Section 10.2.6(b)</u> will terminate or otherwise affect the provisions of this Agreement with respect to the Brain Shuttle Development Candidate-R&amp;D Plan, which shall remain
                    in full force and effect.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zfb67b16b5a4e4070bbdd1c50e2c598ed">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">10.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Alternative Remedies to Termination Available to Roche Prior to Option Exercise</u></font><font style="font-size: 10pt;">. If, prior to Option exercise,
                    Roche elects to exercise the alternative remedy provisions of this <u>Section 10.3</u> in lieu of terminating this Agreement by providing written notice of such election to Isis in accordance with <u>Section 10.2.3(a)</u>, then this
                    Agreement will continue in full force and effect with the following modifications:</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="za0960048cd09423d8b8abacdf6dae772">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Isis will have no further obligations under the R&amp;D Plans, and Roche is responsible for the continued research, Development and Commercialization of Products (including meeting all remaining performance obligations under <u>ARTICLE


                    1</u> and <u>Section 5.1</u>);</div>
              </td>
            </tr>

        </table>
        <div>&#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="zd8b40c3daf7a4c0aa35b05eeffeb0c5c">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>effective as of the date of Roche&#8217;s notice to Isis electing the alternative remedy provisions of this <u>Section 10.3</u>, Roche will be deemed for all purposes of this Agreement to have exercised the Option;</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">56</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z509cb6e3709d45a3a93f5833b1ff5bc4">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(c)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Roche will have and Isis grants, the exclusive license under <u>Section 4.1.1</u>;</div>
              </td>
            </tr>

        </table>
        <div>&#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="ze4b74b4643394f808f8244c3b6c6cd46">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(d)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Isis will perform its obligations under <u>Section 4.2</u> within sixty (60) days of Roche electing to exercise its alternative remedies under this <u>Section 10.3</u>; and</div>
              </td>
            </tr>

        </table>
        <div>&#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="z997575e714ba4e56873a11fafb6fc66b">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(e)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>the financial provisions of <u>ARTICLE 6</u> will be modified as follows:</div>
              </td>
            </tr>

        </table>
        <div>&#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="ze62a7031ae834d24bfbb325ced19f442">

            <tr>
              <td style="width: 108pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(i)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt;"><u>[</u>***<u>]</u><font style="font-style: italic;"><u> Payments</u></font>. Roche will [***]; and</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z123056e895bd414997431d5ab151dea2">

            <tr>
              <td style="width: 108pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(ii)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-style: italic;"><u>License Fee</u></font><font style="font-size: 10pt;">. The license fee set forth in <u>Section 6.3</u> will be [***]. Such [***] will be due within [***]
                    after the [***] but in no event later than [***].</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="text-align: justify; text-indent: 36pt;">The milestone provisions of <u>Section 6.4</u> and <u>Section 6.5</u> and the royalty provisions of <u>Section 6.7</u> will [***].</div>
        <div>&#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="z0a4e82edacbe43c78d29c6732383da68">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">10.4.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Consequences of Expiration or Termination of the Agreement</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z76010cd7317744b3ada62d2b0ff6072c">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">10.4.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>In General</u></font><font style="font-size: 10pt;">. If this Agreement expires or is terminated by a Party in accordance with this <u>ARTICLE 10</u> at any
                    time and for any reason, the following terms will apply to any such expiration or termination:</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z0782ca7272c54ecf9715bc00de328b46">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Return of Information and Materials</u></font><font style="font-size: 10pt;">. The Parties will return (or destroy, as directed by the other Party) all data,
                    files, records and other materials containing or comprising the other Party&#8217;s Confidential Information that are the subject of such termination. Notwithstanding the foregoing, the Parties will be permitted to retain one copy of such
                    data, files, records, and other materials for archival and legal compliance purposes.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z67fd24bd066c433a9522c2561520b76c">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>License Termination</u></font><font style="font-size: 10pt;">. Except for the licenses granted under <u>Section 4.1.2</u>, any licenses granted by Isis to
                    Roche under this Agreement will terminate and Roche, its Affiliates and Sublicensees will cease selling all Products.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z8eb5d9e719ef46ffb9b6a14d88e38ce3">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(c)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Exclusivity Covenants</u></font><font style="font-size: 10pt;">. Neither Party will have any further obligations under <u>Section 2.1.1</u> of this
                    Agreement.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z4c93548a69a44f678e122a1b1b28408d">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(d)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Accrued Rights</u></font><font style="font-size: 10pt;">.<font style="font-weight: bold;">&#160;</font>Termination or expiration of this Agreement for any reason
                    will be without prejudice to any rights or financial compensation that will have accrued to the benefit of a Party prior to such termination or expiration. Such termination or expiration will not relieve a Party from obligations that
                    are expressly indicated to survive the termination or expiration of this Agreement. For purposes of clarification, milestone payments under <u>ARTICLE 6</u> accrue as of the date the applicable Milestone Event is achieved even if the
                    payment is not due at that time.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">57</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z66ae7bf1cdac4232a2965aec47d0448e">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(e)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Survival</u></font><font style="font-size: 10pt;">. The following provisions of this Agreement will survive the expiration or termination of this Agreement:
                    <u>Section 1.12</u> (Failure to Designate an Isis Development Candidate) (but only if this Agreement is terminated under <u>Section 10.2.6(b)</u> with respect to the Isis Development Candidate-R&amp;D Plan); <u>Section 4.1.2</u>
                    (Brain Shuttle IP Licenses); <u>Section </u><u>4.1.4(d</u>) (Effect of Termination on Sublicenses), <u>Section 4.2</u> (Technology Transfer after Option Exercise) (but only to the extent necessary to satisfy the requirements of <u>Section


                      10.4.2</u>), <u>Section </u><u>6.10</u> (Reverse Royalty Payments to Roche for a Discontinued Product), <u>Section 6.12.5</u> (Records Retention), <u>Section 6.13</u> (Audits), <u>Section 7.1.1</u> (Isis Technology and Roche
                    Technology), <u>Section 7.1.2</u> (Agreement Technology), <u>Section 8.5</u> (Disclaimer), <u>ARTICLE 9</u> (Indemnification; Insurance), <u>Section 10.1</u> (Agreement Term; Expiration), <u>Section 10.2.1</u> (Roche&#8217;s Termination
                    for Convenience), <u>Section 10.2.5</u> (Termination for Insolvency), <u>Section 10.4</u> (Consequences of Expiration or Termination of the Agreement), <u>ARTICLE 11</u> (Confidentiality), <u>ARTICLE 12</u> (Miscellaneous) and <u><font style="font-variant: small-caps;">Appendix 1</font></u> (Definitions) (to the extent definitions are embodied in the foregoing listed Articles and Sections).</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z182383dff2ed43779bb25320fcd51393">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">10.4.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Special Consequences of Expiration or Termination of the Agreement</u></font><font style="font-size: 10pt;">. If (A) this Agreement expires due to the
                    expiration of Roche&#8217;s Option under <u>Section 3.2</u>, (B) Roche terminates the Agreement under <u>Section 10.2.1 </u>(Roche&#8217;s Termination for Convenience), or (C) Isis terminates this Agreement under <u>Section 7.12</u> (No
                    Challenge), <u>Section </u><u>10.2.2(b</u>) (Isis&#8217; Right to Terminate) or <u>Section </u><u>10.2.3(b</u>) (Remedies for Failure to Use Commercially Reasonable Efforts), then the following additional terms will also apply:</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z8c1250aa8a7d4feb9caf1cdf9b619cc0">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>License to Isis for Isis Development Candidates</u></font><font style="font-size: 10pt;">. Roche will and hereby does grant to Isis a
                    sublicensable, worldwide, exclusive license or sublicense, as the case may be, under all Roche Technology (excluding Companion Diagnostic IP) Controlled by Roche as of the date of such reversion that Covers Discontinued Products
                    comprising an Isis Development Candidate solely as necessary to Develop, make, have made, use, sell, offer for sale, have sold, import and otherwise Commercialize such Discontinued Products in the Field;</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z657accd447a441a2a42af075e0b60422">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>License to Isis for Brain Shuttle Development Candidates</u></font><font style="font-size: 10pt;">. Roche will and hereby does grant to
                    Isis a sublicensable, worldwide, non-exclusive license or sublicense, as the case may be, under all Roche Technology (excluding Companion Diagnostic IP) Controlled by Roche as of the date of such reversion that Covers Discontinued
                    Products comprising a Brain Shuttle Development Candidate solely as necessary to Develop, make, have made, use, sell, offer for sale, have sold, import and otherwise Commercialize such Discontinued Products in the Field;</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">58</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z1707dd5cc4dd4262994ab25c2343f31c">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(c)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>License to Isis for Companion Diagnostic Products</u></font><font style="font-size: 10pt;">. Roche will make available to Isis, on
                    commercially reasonable terms, any diagnostic products and/or services to select patients who will use Products (each, a &#8220;<font style="font-weight: bold; font-style: italic;">Companion Diagnostic Product</font>&#8221;) and any Patent Rights
                    and Know-How Covering such Companion Diagnostic Products (such intellectual property, &#8220;<font style="font-weight: bold; font-style: italic;">Companion Diagnostic IP</font>&#8221;) Controlled by Roche as of the date of such reversion that is
                    necessary to Develop or Commercialize such Companion Diagnostic Products;</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z893835763d7f4213a6245f9fc284c7c5">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(d)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Know-How Transfer</u></font><font style="font-size: 10pt;">. Roche will transfer to Isis for use with respect to the Development and
                    Commercialization of Discontinued Products, copies of any Know-How data, results, regulatory information, filings, and files in the possession of Roche as of the date of such reversion that relate to such Discontinued Products and are
                    necessary for the Development of such Discontinued Products, and any other information or material specified in <u>Section </u><u>4.2</u>;</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zd9e3dcbf5ae64ccfb3469dfcc798fd40">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(e)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Trademarks</u></font><font style="font-size: 10pt;">. Roche will license to Isis any trademarks that are specific to Discontinued
                    Products solely for use with such Discontinued Products; <font style="font-style: italic;">provided, however</font>, that in no event will Roche have any obligation to license to Isis any trademarks used by Roche both in connection
                    with a Product and in connection with the sale of any other product or service, including any Roche- or Roche-formative marks, company logos, or trademarks of its Affiliates or Sublicensees; and</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z6a53b93aeeb647e0b8374a59a539397f">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(f)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold; font-style: italic;"><u>Prosecution and Maintenance</u></font><font style="font-size: 10pt;">. Isis will control and be responsible at its sole cost for all
                    aspects of the Prosecution and Maintenance of all Jointly-Owned Collaboration Patents, and Roche will provide Isis with (and will instruct its counsel to provide Isis with) all of the information and records in Roche&#8217;s and its counsel&#8217;s
                    possession related to the Prosecution and Maintenance of such Jointly-Owned Collaboration Patents.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="text-align: center; font-weight: bold;">ARTICLE 11.</div>
        <div style="text-align: center; font-weight: bold;">CONFIDENTIALITY</div>
        <div>&#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="ze3219bb6d94c4c1abc04ad812fc359ae">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">11.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Confidentiality; Exceptions</u></font><font style="font-size: 10pt;">. Except to the extent expressly authorized by this Agreement or otherwise agreed in
                    writing, the Parties agree that, during the Agreement Term and for five years thereafter, the receiving Party (the &#8220;<font style="font-weight: bold; font-style: italic;">Receiving Party</font>&#8221;) and its Affiliates 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 <font style="color: rgb(0, 0, 0);">or</font> proprietary information or materials, patentable or otherwise,
                    in any form (written, oral, photographic, electronic, magnetic, or otherwise) which is disclosed to it by the other Party (the &#8220;<font style="font-weight: bold; font-style: italic;">Disclosing Party</font>&#8221;) or its Affiliates or
                    otherwise received or accessed by a Receiving Party in the course of performing its obligations or exercising its rights under this Agreement, including trade secrets, Know-How, inventions or discoveries, proprietary information,
                    formulae, processes, techniques and information relating to the past, present and future marketing, financial, and research and development activities of any product or potential product or useful technology of the Disclosing Party or
                    its Affiliates and the pricing thereof (collectively, &#8220;<font style="font-weight: bold; font-style: italic;">Confidential Information</font>&#8221;).</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">59</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z1d266a510be34bed94478c050f0937b4">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">11.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Prior Confidentiality Agreement</u></font><font style="font-size: 10pt;">. The Non-Disclosure Agreement executed by Isis and Roche on February 1, 2012
                    (including any and all amendments thereto) (the &#8220;<font style="font-weight: bold; font-style: italic;">CDA</font>&#8221;) will govern disclosures of Information (as defined in the CDA) between the Parties prior to the Effective Date. All
                    Confidential Information exchanged between the Parties on or after the Effective Date under this Agreement will be subject to the terms of this <u>ARTICLE 11</u>.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="za47eaa50a7084a459e2af6532fc494a3">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">11.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Authorized Disclosure</u></font><font style="font-size: 10pt;">. Except as expressly provided otherwise in this Agreement, a Receiving Party or its
                    Affiliates may use and disclose to Third Parties Confidential Information of the Disclosing Party as follows: (i) solely in connection with the performance of its obligations or exercise of rights granted or reserved in this Agreement
                    under confidentiality provisions no less restrictive than those in this Agreement, <font style="font-style: italic;">provided, </font>a Receiving Party may disclose Confidential Information to a governmental entity or agency without
                    requiring such entity or agency to enter into a confidentiality agreement; (ii) to the extent reasonably necessary to file or prosecute patent, copyright and trademark applications (subject to <u>Section 11.4</u> below), complying with
                    applicable governmental regulations, obtaining Approvals, conducting Pre-Clinical Studies or Clinical Studies, marketing a Product, or as otherwise required by applicable law, regulation, rule or legal process (including the rules of
                    the SEC and any stock exchange); <font style="font-style: italic;">provided, however</font>, that if a Receiving Party or any of its Affiliates is required by law or regulation to make any such disclosure of a Disclosing Party&#8217;s
                    Confidential Information it will, except where impracticable for necessary disclosures, give reasonable advance notice to the Disclosing Party of such disclosure requirement and will use its reasonable efforts to secure confidential
                    treatment of such Confidential Information required to be disclosed; (iii) in communication with actual or potential lenders, investors, merger partners, acquirers, consultants, or professional advisors on a need-to-know basis, in each
                    case under confidentiality provisions no less restrictive than those of this Agreement; (iv) to the extent such disclosure is required to comply with existing expressly stated contractual obligations owed to such Party&#8217;s or its
                    Affiliates&#8217; licensor with respect to any intellectual property licensed to the other Party under this Agreement; or (v) as mutually agreed to in writing by the Parties.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z40899b9072914d61ba1b0978d2597afc">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">11.4.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Press Release; Publications; Disclosure of Agreement</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z10a5a4d498fd414385c76b56ca26e96c">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">11.4.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Public Announcements &#8211; Generally</u></font><font style="font-size: 10pt;">. Upon execution of this Agreement, the Parties will issue a joint press release
                    announcing the existence of this Agreement in a form and substance agreed to in writing by the Parties. Except to the extent required to comply with Applicable Law, regulation, rule or legal process or as otherwise permitted in
                    accordance with this <u>Section 11.4</u>, each Party agrees not to issue any other press release or other public statement disclosing other information relating to this Agreement or the terms of this Agreement or the transactions
                    contemplated hereby without the prior written consent of the other Party, which consent will not be unreasonably withheld or delayed.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">60</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z78f948fc4f09456da00a4550efbf624e">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">11.4.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Use of Name</u></font><font style="font-size: 10pt;">.<font style="font-weight: bold;">&#160;</font>Except as set forth in <u>Section 11.4.9</u>, neither Party
                    will use the other Party&#8217;s name in a press release or other publication without first obtaining the prior consent of the Party to be named.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="ze4dd8dd0edbd4988a535d4f84d91a574">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">11.4.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Notice of Significant Events</u></font><font style="font-size: 10pt;">. Each Party will notify (no later than three Business Days after the information or
                    results are obtained) the other Party of any significant event related to a Product (including any data, serious adverse event or regulatory advice or approval) so that the Parties may analyze the need to or desirability of publicly
                    disclosing or reporting such event. Notwithstanding <u>Section 11.4.1</u> above, any press release or other similar public communication by either Party related to a Product&#8217;s efficacy or safety data and/or results, will be submitted
                    to the other Party for review and approval at least three Business Days in advance of such proposed public disclosure, which approval will not be unreasonably withheld or delayed.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z122c083f531b471f9b9cc4fb94459950">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">11.4.4.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Prior to Option Exercise</u></font><font style="font-size: 10pt;">. Prior to Option exercise, Isis will have the sole right, consistent with its practice
                    with its other compounds and products, to issue press releases, publish, present or otherwise disclose the progress and results regarding the Products to the public; <font style="font-style: italic;">provided</font>, that with respect
                    to any proposed press release or other similar public communication by Isis disclosing regulatory discussions, the efficacy or safety data <font style="color: rgb(0, 0, 0);">or</font> clinical results related to the Products, (i) Isis
                    will submit such proposed communication to Roche for review at least ten (10)&#160; Business Days in advance of such proposed public disclosure, (ii) Roche will have the right to review and recommend changes to such communication, and (iii)
                    Isis will in good faith consider any changes that are timely recommended by Roche.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z38b70e3f5531411faaea6be70a68d8d7">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">11.4.5.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>After Option Exercise</u></font><font style="font-size: 10pt;">. After Option exercise, Roche will have the sole right, consistent with its practice with its
                    other compounds and products, to issue press releases, publish, present or otherwise disclose the progress and results regarding the Products to the public; <font style="font-style: italic;">provided</font>, that with respect to any
                    proposed press release or other similar public communication by Roche disclosing regulatory discussions, the efficacy or safety data <font style="color: rgb(0, 0, 0);">or</font> results related to the Products or Roche&#8217;s sales
                    projections, (i) Roche will submit such proposed communication to Isis for review at least two Business Days in advance of such proposed public disclosure, (ii) Isis will have the right to review and recommend changes to such
                    communication, and (iii) Roche will in good faith consider any changes that are timely recommended by Isis.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">61</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="z34a2150f4f1b4d378c8751cacbca29f1">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">11.4.6.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Scientific or Clinical Presentations</u></font><font style="font-size: 10pt;">. Regarding any proposed scientific publications related to results from any
                    Clinical Studies, the Parties agree to use Commercially Reasonable Efforts to control public scientific disclosures of such results to prevent any adverse effect of any premature public disclosure of such results. The Parties will
                    establish a procedure for publication review and each Party will first submit to the other Party through the Joint Patent Committee an early draft of all such publications or presentations, at least forty-five (45) days prior to
                    submission for publication including to facilitate the publication of any summaries of Clinical Studies data and results as required on the clinical trial registry of each respective Party. Each Party will review such proposed
                    publication to avoid the unauthorized disclosure of a Party&#8217;s Confidential Information and to preserve the patentability of inventions arising from an R&amp;D Plan. If, during such forty-five (45) day period, the other Party informs
                    such Party that its proposed publication contains Confidential Information of the other Party, then such Party will delete such Confidential Information from its proposed publication. In addition, if during such forty-five (45) day
                    period, the other Party informs such Party that its proposed publication discloses non-public inventions made by either Party in the course of the Development under this Agreement, or the public disclosure of such proposed publication
                    may have a material adverse effect on any Patent Rights or Know-How solely owned or Controlled by such other Party, then such Party will either (i) delay such proposed publication for up to sixty (60) days from the date of such Party&#8217;s
                    objection, to permit the timely first filing of patent application(s), or (ii) remove the identified disclosures prior to publication.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z60f8384b382f473f969ad69390d4f23f">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">11.4.7</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>SEC Filings</u></font><font style="font-size: 10pt;">. Each Party will give the other Party a reasonable opportunity to review all material filings with the
                    SEC describing the terms of this Agreement prior to submission of such filings, and will give due consideration to any reasonable comments by the non-filing Party relating to such filing.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zef299c0a396344ad8c38b59fdce03369">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">11.4.8</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Subsequent Disclosure</u></font><font style="font-size: 10pt;">. Notwithstanding the foregoing, to the extent information regarding this Agreement or a
                    Product has already been publicly disclosed, either Party (or its Affiliates) may subsequently disclose the same information to the public without the consent of the other Party.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zd13ee5f415e04bfea9253b78f3f2840c">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">11.4.9</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Acknowledgment; Commercial Materials</u></font><font style="font-size: 10pt;">. Each Party will acknowledge in any press release, public presentation,
                    publication or commercial marketing materials regarding the collaboration <font style="color: rgb(0, 0, 0);">or</font> a Product, the other Party&#8217;s role in discovering and developing a Product <font style="color: rgb(0, 0, 0);">or</font>
                    Discontinued Product, as applicable, that the Product is under license from Isis and otherwise acknowledge the contributions from the other Party, and each Party&#8217;s stock ticker symbol (<u>e.g.</u>, Isis: Nasdaq: ISIS; Roche: SIX: RO,
                    ROG; OTCQX: RHHBY). Isis may include the Products (and identify Roche as its partner for the Product) in Isis&#8217; drug pipeline.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">62</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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;">ARTICLE 12.</div>
        <div style="text-align: center; font-weight: bold;">MISCELLANEOUS</div>
        <div>&#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="z666d9631eaef4fdba69c3b5f0ed6937e">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">12.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Dispute Resolution</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zf2f827562b3b44d0b5c6e17d7656e428">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">12.1.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Escalation</u></font><font style="font-size: 10pt;">. If any dispute occurs under this Agreement (other than a dispute regarding the construction, validity
                    or enforcement of either Party&#8217;s Patents, which disputes will be resolved pursuant to <u>Section 12.2</u>), either Party may request in writing that the dispute be referred for resolution to the Head of Roche Partnering of Roche and
                    the COO of Isis (the &#8220;<font style="font-weight: bold; font-style: italic;">Executives</font>&#8221;). Within thirty (30) days after such a request, the Executives will meet in person at a mutually acceptable time and location or by means of
                    telephone or video conference to negotiate a settlement of the dispute. Each Party&#8217;s JSC representatives may participate in such meeting if desired. If the Executives fail to resolve the dispute within such thirty (30) day period, then
                    the dispute will be referred to binding arbitration under <u>Section 12.1.2</u>.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z35c25588dbe34a368be471c57925aa44">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">12.1.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Binding Arbitration</u></font><font style="font-size: 10pt;">. If a dispute subject to <u>Section 12.1.1</u> is not resolved pursuant to <u>Section 12.1.1</u>,
                    such dispute will be resolved through binding arbitration in accordance with this <u>Section 12.1.2</u> and under the Commercial Arbitration Rules of the American Arbitration Association (&#8220;<font style="font-weight: bold; font-style: italic;">AAA</font>&#8221;) then in effect, including application of the &#8220;<font style="font-style: italic;">Expedited Procedures</font>&#8221; (sections E-1, et al) of the Commercial Arbitration Rules of the AAA. The proceedings and decisions of
                    the arbitrator will be confidential, final and binding on the Parties, and judgment upon the award of such arbitrators may be entered in any court having jurisdiction thereof. The arbitration will take place in Boston, Massachusetts USA
                    and will be conducted by three (3) arbitrators. Each of Roche and Isis shall appoint one (1) arbitrator within thirty (30) days after the notice that initiated the arbitration. These two (2) arbitrators shall in turn appoint a third
                    arbitrator who will be reasonably acceptable to the Parties and who will be appointed in accordance with AAA rules. Each arbitrator chosen hereunder will have educational training and industry experience sufficient to demonstrate a
                    reasonable level of scientific, financial, medical and industry knowledge relevant to the particular dispute.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zd0f6cb290ea542c2b2ed61d36d72d0ab">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">12.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Governing Law; Jurisdiction; Venue; Service of Process</u></font><font style="font-size: 10pt;">.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z08a60b80b6bd4ac7aeca159ad930fc40">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">12.2.1.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>This Agreement and any dispute will be governed by and construed and enforced in accordance with the laws of the State of California, U.S.A., without reference to conflicts of laws principles.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z1c95f4d812dd4e70b22faabaf28685d8">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">12.2.2.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Each Party hereby agrees that service of process: (a) made in any manner permitted by California law, or (b) made by overnight express courier service (signature required), prepaid, at its address specified pursuant to <u>Section 12.7</u>,
                  will constitute good and valid service of process in any such action and (c) waives and agrees not to assert (by way of motion, as a defense, or otherwise) in any such action any claim that service of process made in accordance with
                  clause (a) or (b) does not constitute good and valid service of process.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z6491324cf66948c5a0a47e25f9104252">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">12.3.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Remedies</u></font><font style="font-size: 10pt;">. Notwithstanding anything to the contrary in this Agreement, 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 restraining order or a preliminary injunction, without the posting of any bond or other security, enjoining or restraining the other Party from any
                    violation or threatened violation of this Agreement, and the Parties agree that in the event of a threatened or actual material breach of this Agreement injunctive relief would be appropriate. Neither Party may 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


                      9.1</u> or <u>Section 9.2</u>). Except for the offsets and credits explicitly set forth in <u>Section </u><u>6.11.3(b</u>) and <u>Section 6.13</u>, neither Party will have the right to setoff any amount it is owed or believes it
                    is owed against payments due or payable to the other Party under this Agreement.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">63</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="zbed14696799f4937870d6054112f70ed">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">12.4.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Assignment and Successors</u></font><font style="font-size: 10pt;">. Neither this Agreement nor any obligation of a Party hereunder may be assigned by either
                    Party without the consent of the other, 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 or all or substantially all of its assets to which this Agreement relates or to any successor corporation resulting from any merger, consolidation, share exchange or other similar
                    transaction; <font style="font-style: italic;">provided</font>, if a Party transfers or assigns this Agreement to [***] described in this Agreement, then such transferring Party (or such Affiliate) (&#8220;<font style="font-weight: bold; font-style: italic;">Transferring Party</font>&#8221;), will [***] that the Transferring Party is obligated to pay to the non-transferring Party (&#8220;<font style="font-weight: bold; font-style: italic;">Non-Transferring Party</font>&#8221;) under <u>ARTICLE


                      6</u> for the taxes withheld such that the Non-Transferring Party receives [***] assignment. In addition, Isis may assign or transfer its rights to receive payments under this Agreement (but no liabilities), without Roche&#8217;s consent,
                    to an Affiliate or to a Third Party in connection with a payment factoring transaction. Any purported assignment or transfer made in contravention of this <u>Section 12.4</u> will be null and void.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="text-align: justify; margin-left: 36pt;">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&#160; in determining when
          [***] pursuant to the foregoing sentence, beginning with the first Annual tax return for the year in which the [***] payment under this <u>Section 12.4</u>, and each year thereafter (including, for clarity, all years in which the
          Non-Transferring Party utilizes a [***]), the Non-Transferring Party will provide the Transferring Party&#160; with&#160; the Non-Transferring Party s&#8217; Annual tax returns (federal and state) and, in years in which the Non-Transferring Party utilizes the
          [***], supporting documentation for such [***].</div>
        <div>&#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="z82d722945ca64b26a11ed6944aa23bb7">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">12.5.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Change of Control</u></font><font style="font-size: 10pt;">. If Isis undergoes a Change of Control, then Roche shall have the right at any time after it
                    exercises the Option to disband the JSC and make unilateral decisions with respect to the R&amp;D Plan, Development and Commercialization with no obligation to seek input from Isis or its successor, if applicable.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">64</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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="ze325cc9307774d19aedd20e56b06a2ba">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">12.6.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Force Majeure</u></font><font style="font-size: 10pt;">. No Party will be held 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 performing any obligation of this Agreement when such failure or delay is due to force majeure, and without the fault or negligence of the Party so failing or delaying.
                    For purposes of this Agreement, force majeure means a cause beyond the reasonable control of a Party, which may include acts of God; acts, regulations, or laws of any government; war; terrorism; civil commotion; fire, flood, earthquake,
                    tornado, tsunami, explosion or storm; pandemic; epidemic and failure of public utilities or common carriers. In such event the Party so failing or delaying 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 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 ninety (90) days, after which time the Parties will negotiate in good faith any modifications of the terms of this Agreement that may be necessary to arrive at an equitable solution, unless the Party giving such notice has set out a
                    reasonable timeframe and plan to resolve the effects of such force majeure and executes such plan within such timeframe.&#160; To the extent possible, each Party will use reasonable efforts to minimize the duration of any force majeure.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z43fefa9ddd614b62bfee1c21063648f4">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">12.7.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Notices</u></font><font style="font-size: 10pt;">. 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), facsimile transmission (receipt verified), 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>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div>
          <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zf34d36924d154e3094f6879faed5db3f" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

              <tr style="vertical-align: top;">
                <td style="width: 36pt;">&#160;</td>
                <td style="vertical-align: top; width: 178pt;">
                  <div style="text-align: left;">If to Isis, addressed to: <br>
                  </div>
                </td>
                <td style="vertical-align: top; width: auto;">
                  <div style="text-align: left;">Isis Pharmaceuticals, Inc.</div>
                </td>
              </tr>

          </table>
        </div>
        <div style="text-indent: 180pt; margin-left: 36pt;">2855 Gazelle Court</div>
        <div style="text-indent: 180pt; margin-left: 36pt;">Carlsbad, CA&#160; 92010</div>
        <div style="text-indent: 180pt; margin-left: 36pt;">Attention:&#160; Chief Operating Officer</div>
        <div style="text-indent: 180pt; margin-left: 36pt;">Fax:&#160; 760-918-3592</div>
        <div><br>
        </div>
        <div>
          <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z6ad7fe421cff48d4ae52917bb8f81585" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

              <tr style="vertical-align: top;">
                <td style="width: 36pt;">&#160;</td>
                <td style="vertical-align: top; width: 178pt;">
                  <div style="text-align: left;">with a copy to:</div>
                </td>
                <td style="vertical-align: top; width: auto;">
                  <div style="text-align: left;">Isis Pharmaceuticals, Inc.</div>
                </td>
              </tr>

          </table>
        </div>
        <div style="text-indent: 180pt; margin-left: 36pt;">2855 Gazelle Court</div>
        <div style="text-indent: 180pt; margin-left: 36pt;">Carlsbad, CA&#160; 92010</div>
        <div style="text-indent: 180pt; margin-left: 36pt;">Attention:&#160; General Counsel</div>
        <div style="text-indent: 180pt; margin-left: 36pt;">Fax:&#160; 760-268-4922</div>
        <div><br>
        </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="z8520f6854f294010876ebe7d20bee67d">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 178pt; vertical-align: top;">If to Roche, addressed to:</td>
              <td style="width: auto; vertical-align: top;">
                <div>F. Hoffmann-La Roche Ltd</div>
              </td>
            </tr>

        </table>
        <div style="text-indent: 0pt; margin-left: 216pt;">Grenzacherstrasse 124</div>
        <div style="margin-left: 216pt;">4070 Basel, Switzerland</div>
        <div style="margin-left: 216pt;">Attention:&#160; Corporate Legal Department</div>
        <div style="margin-left: 216pt;">Fax:&#160; +41 61 688 13 96</div>
        <div><br>
        </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="z103bcc11aeda41238d91f6a4193a5491">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 178pt; vertical-align: top;">If to Roche, addressed to:</td>
              <td style="width: auto; vertical-align: top;">
                <div>Hoffmann-La Roche Inc.</div>
              </td>
            </tr>

        </table>
        <div style="text-indent: 0pt; margin-left: 216pt;">340 Kingsland Street</div>
        <div style="margin-left: 216pt;">Nutley, New Jersey 07110</div>
        <div style="margin-left: 216pt;">Attention:&#160; Corporate Secretary</div>
        <div style="margin-left: 216pt;">Fax:&#160; 973-235-3500</div>
        <div><br>
        </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="ze49c657c9167450f87b57a29edf425a8">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 178pt; vertical-align: top;">with a copy to:</td>
              <td style="width: auto; vertical-align: top;">
                <div>F. Hoffmann-La Roche Ltd</div>
              </td>
            </tr>

        </table>
        <div style="text-indent: 0pt; margin-left: 216pt;">Grenzacherstrasse 124</div>
        <div style="margin-left: 216pt;">4070 Basel, Switzerland</div>
        <div style="margin-left: 216pt;">Attention:&#160; Alliance Manager</div>
        <div style="margin-left: 216pt;">Fax:&#160; +41 61 688 30 50</div>
        <div style="margin-left: 216pt;"> <br>
        </div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">65</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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; margin-left: 36pt;">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 that</font> notices of a change of address will be
          effective only upon receipt thereof.&#160; If delivered personally or by facsimile transmission, the date of delivery will be deemed to be the date on which such notice or request was given.&#160; If sent by overnight express courier service, the date of
          delivery will be deemed to be the next Business Day after such notice or request was deposited with such service.&#160; If sent by certified mail, 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.</div>
        <div>&#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="zaa1ade4751294b91a9eb509c79d9cb21">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">12.8.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Invoices</u></font><font style="font-size: 10pt;">.&#160; All invoices that are required or permitted hereunder shall be in writing and sent by Isis to Roche at
                    the following address or any other address that Roche may later provide:</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="text-align: justify; margin-left: 36pt;">F. Hoffmann-La Roche AG</div>
        <div style="text-align: justify; margin-left: 36pt;">Kreditorenbuchhaltung</div>
        <div style="text-align: justify; margin-left: 36pt;">4070 Basel</div>
        <div style="text-align: justify; margin-left: 36pt;">Switzerland</div>
        <div>&#160;</div>
        <div style="text-align: justify; margin-left: 36pt;">with an electronic copy to Roche&#8217;s Alliance Manager.</div>
        <div>&#160;</div>
        <div style="text-align: justify; margin-left: 36pt;">Upon Isis&#8217; request, Roche&#8217;s Alliance Manager will provide Isis&#8217; Alliance Manager with any additional information reasonably requested by Isis to facilitate the prompt delivery of invoices to
          Roche, including a facsimile number for sending invoices.</div>
        <div>&#160;</div>
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            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">12.9.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Export Clause</u></font><font style="font-size: 10pt;">. Each Party acknowledges that the laws and regulations of the United States restrict the export and
                    re-export of commodities and technical data of United States origin.&#160; 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>
              </td>
            </tr>

        </table>
        <div>&#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="zba7538aaf66047f68e1ea4d4bb0ac24f">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">12.10.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Waiver</u></font><font style="font-size: 10pt;">. Neither Party may waive or release any of its rights or interests in this Agreement except in writing.&#160; 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.&#160; No waiver by either Party of any condition or term in any one or more instances will be construed as a continuing waiver or subsequent waiver of such condition or term or of another condition or term.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z32bea259d5ce4e6486bcb5784edc8fbd">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">12.11.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Severability</u></font><font style="font-size: 10pt;">. If any provision hereof should be held invalid, illegal or unenforceable in any jurisdiction, 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 hereto 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>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">66</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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: 36pt; vertical-align: top; font-weight: bold;">12.12.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Entire Agreement</u></font><font style="font-size: 10pt;">. This Agreement, together with the Schedules and Appendices hereto, sets forth all the covenants,
                    promises, agreements, warranties, representations, conditions and understandings between the Parties and supersedes and terminates all prior agreements and understanding between the Parties. There are no covenants, promises, agreements,
                    warranties, representations, conditions or understandings, either oral or written, between the Parties other than as set forth herein and therein.&#160; No subsequent alteration, amendment, change or addition to this Agreement will be
                    binding upon the Parties hereto unless reduced to writing and signed by the respective authorized officers of the Parties.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z9a24a3c017a8498dbbc66803f715a44b">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">12.13.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Independent Contractors</u></font><font style="font-size: 10pt;">. 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. Neither Party will assume, either directly or indirectly, any liability of or for the other Party.&#160; 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>
              </td>
            </tr>

        </table>
        <div>&#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="z7da1a501ba7647b985ae7ea20e1a92ec">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">12.14.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Interpretation</u></font><font style="font-size: 10pt;">. Except as otherwise explicitly specified to the contrary, (a) references to a section, exhibit or
                    schedule means a section of, or schedule or exhibit to this Agreement, unless another agreement is specified, (b) the word &#8220;including&#8221; (in its various forms) means &#8220;including without limitation,&#8221; (c) the words &#8220;will&#8221; and &#8220;shall&#8221; have
                    the same meaning, (d) references to a particular statute or regulation include all rules and regulations thereunder and any predecessor or successor statute, rules or regulation, in each case as amended or otherwise modified from time
                    to time, (e) words in the singular or plural form include the plural and singular form, respectively, (f) references to a particular Person include such Person&#8217;s successors and assigns to the extent not prohibited by this Agreement, (g)
                    unless otherwise specified, &#8220;$&#8221; is in reference to United States dollars, and (h) the headings contained in this Agreement, in any exhibit or schedule to this Agreement and in the table of contents to this Agreement are for convenience
                    only and will not in any way affect the construction of or be taken into consideration in interpreting this Agreement.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zb5faaeaed85047448dae79f04de82d97">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">12.15.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Further Actions</u></font><font style="font-size: 10pt;">. 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>
              </td>
            </tr>

        </table>
        <div>&#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="z968e095978a542a09a71eff28475de1a">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">12.16.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Construction of Agreement</u></font><font style="font-size: 10pt;">.<font style="font-weight: bold;">&#160;</font>The terms and provisions 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 provisions of this Agreement will be interpreted and construed in accordance with their usual and customary meanings, and each of the Parties hereto 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.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">67</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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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        <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z9919192ee9e4434893a40af749c01f69">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">12.17.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Supremacy</u></font><font style="font-size: 10pt;">. In the event of any express conflict or inconsistency between this Agreement and any Schedule or
                    Appendix hereto, the terms of this Agreement will apply. The Parties understand and agree that the Schedules and Appendices hereto are not intended to be the final and complete embodiment of any terms or provisions of this Agreement,
                    and are to be updated from time to time during the Agreement Term, as appropriate and in accordance with the provisions of this Agreement.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="z2d33e6efe49745c692ce9a937e318043">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">12.18.</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;"><u>Counterparts</u></font><font style="font-size: 10pt;">. This Agreement may be signed in counterparts, each 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 of this Agreement from separate computers or printers. Facsimile signatures and signatures
                    transmitted via electronic mail in PDF format will be treated as original signatures.</font></div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="text-align: center; font-style: italic;">[SIGNATURE PAGES FOLLOW]</div>
        <div>&#160;</div>
        <div style="text-align: center;">* - * - * - *</div>
        <div style="text-align: center;"> <br>
        </div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">68</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;">IN WITNESS WHEREOF</font><font style="font-size: 10pt;">, the Parties have caused this Agreement to be executed by their
            representatives thereunto duly authorized as of the Effective Date.</font></div>
        <div><br>
        </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="z5837a9f58c344592b705f0dd4b173dd6">

            <tr>
              <td style="vertical-align: top; width: 50%;">
                <div style="text-align: justify; font-variant: small-caps; font-weight: bold;">F. Hoffmann-La Roche Ltd</div>
              </td>
              <td colspan="1" style="vertical-align: top; width: 50%;"><br>
              </td>
            </tr>

        </table>
        <div><br>
        </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;">

            <tr>
              <td style="width: 3%; vertical-align: top; padding-bottom: 2px;">
                <div style="text-align: justify;">By:</div>
              </td>
              <td style="width: 47%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
              <td colspan="1" style="width: 50%; vertical-align: top; padding-bottom: 2px;"><br>
              </td>
            </tr>

        </table>
        <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;">

            <tr>
              <td style="vertical-align: top; width: 50%;">
                <div style="text-align: justify;">Name:</div>
              </td>
              <td colspan="1" style="vertical-align: top; width: 50%;"><br>
              </td>
            </tr>
            <tr>
              <td style="vertical-align: top; width: 50%;">
                <div style="text-align: justify;">Title:</div>
              </td>
              <td colspan="1" style="vertical-align: top; width: 50%;"><br>
              </td>
            </tr>

        </table>
        <div><br>
        </div>
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            <tr>
              <td style="width: 3%; vertical-align: top; padding-bottom: 2px;">
                <div style="text-align: justify;">By:</div>
              </td>
              <td colspan="1" style="width: 47%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
              <td colspan="1" style="width: 50%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
            </tr>

        </table>
        <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;">

            <tr>
              <td rowspan="1" style="width: 50%; vertical-align: top;">
                <div style="text-align: justify;">Name:</div>
              </td>
              <td colspan="1" rowspan="1" style="width: 50%; vertical-align: top;">&#160;</td>
            </tr>
            <tr>
              <td rowspan="1" style="width: 50%; vertical-align: top;">
                <div style="text-align: justify;">Title:</div>
              </td>
              <td colspan="1" rowspan="1" style="width: 50%; vertical-align: top;">&#160;</td>
            </tr>

        </table>
        <div><br>
        </div>
        <div>
          <div style="text-align: center; font-variant: small-caps; font-weight: bold;">Signature Page to HTT Research, Development, Option and License Agreement</div>
          <div style="text-align: center; font-variant: small-caps; font-weight: bold;"> <br>
          </div>
        </div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">69</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;">IN WITNESS WHEREOF</font><font style="font-size: 10pt;">, the Parties have caused this Agreement to be executed by their
            representatives thereunto duly authorized as of the Effective Date.</font></div>
        <div>&#160;</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;" id="z11d0ae1717e94db99aa1b1119209c352">

            <tr>
              <td style="vertical-align: top; width: 50%;">
                <div style="text-align: justify; font-variant: small-caps; font-weight: bold;">Hoffmann-La Roche Inc.</div>
              </td>
              <td colspan="1" style="width: 50%; vertical-align: top;">&#160;</td>
            </tr>

        </table>
        <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: 3%; vertical-align: top; padding-bottom: 2px;">
                <div style="text-align: justify;">By:</div>
              </td>
              <td style="width: 47%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
              <td colspan="1" style="width: 50%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
            </tr>

        </table>
        <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="vertical-align: top; width: 50%;">
                <div style="text-align: justify;">Name:</div>
              </td>
              <td colspan="1" style="width: 50%; vertical-align: top;">&#160;</td>
            </tr>
            <tr>
              <td style="vertical-align: top; width: 50%;">
                <div style="text-align: justify;">Title:</div>
              </td>
              <td colspan="1" style="width: 50%; vertical-align: top;">&#160;</td>
            </tr>

        </table>
        <div>
          <div style="text-align: center; font-variant: small-caps; font-weight: bold;"> <br>
          </div>
          <div style="text-align: center; font-variant: small-caps; font-weight: bold;">Signature Page to HTT Research, Development, Option and License Agreement</div>
        </div>
        <div><br>
        </div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">70</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: justify; text-indent: 36pt; font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;">IN WITNESS WHEREOF</font><font style="font-size: 10pt;">, the Parties have caused this Agreement to be executed by their
            representatives thereunto duly authorized as of the Effective Date.</font></div>
        <div>&#160;</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;" id="z1ac7ff5e1d9e428c89f086ce68836c0a">

            <tr>
              <td style="vertical-align: top; width: 50%;">
                <div style="text-align: justify; font-variant: small-caps; font-weight: bold;">Isis Pharmaceuticals, Inc.</div>
              </td>
              <td colspan="1" style="width: 50%; vertical-align: top;">&#160;</td>
            </tr>

        </table>
        <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: 3%; vertical-align: top; padding-bottom: 2px;">
                <div style="text-align: justify;">By:</div>
              </td>
              <td style="width: 47%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);"><br>
              </td>
              <td colspan="1" style="width: 50%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
            </tr>

        </table>
        <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 rowspan="1" style="vertical-align: top; width: 50%;">
                <div style="text-align: justify;">Name: B. Lynne Parshall</div>
              </td>
              <td colspan="1" rowspan="1" style="width: 50%; vertical-align: top;">&#160;</td>
            </tr>
            <tr>
              <td rowspan="1" style="vertical-align: top; width: 50%;">
                <div style="text-align: justify;">Title: Chief Operating Officer</div>
              </td>
              <td colspan="1" rowspan="1" style="width: 50%; vertical-align: top;">&#160;</td>
            </tr>

        </table>
        <div><br>
        </div>
        <div>
          <div style="text-align: center; font-variant: small-caps; font-weight: bold;">Signature Page to HTT Research, Development, Option and License Agreement</div>
          <br>
        </div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">71</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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-variant: small-caps; font-weight: bold;"><u>List of Appendices and Schedules</u></div>
        <div>&#160;</div>
        <div style="font-size: 12pt;"><font style="font-size: 10pt; font-variant: small-caps;"><u>Appendix 1</u></font><font style="font-size: 10pt;"> &#8211; Definitions</font></div>
        <div>&#160;</div>
        <div style="font-size: 12pt;"><font style="font-size: 10pt; font-variant: small-caps;"><u>Appendix 2</u></font><font style="font-size: 10pt;"> &#8211; Isis Development Candidate-R&amp;D Plan</font></div>
        <div>&#160;</div>
        <div style="font-size: 12pt;"><font style="font-size: 10pt; font-variant: small-caps;"><u>Appendix 3</u></font><font style="font-size: 10pt;"> &#8211; Brain Shuttle Development Candidate-R&amp;D Plan</font></div>
        <div>&#160;</div>
        <div style="font-size: 12pt;"><font style="font-size: 10pt; font-variant: small-caps;"><u>Appendix 4</u></font><font style="font-size: 10pt;"> &#8211; Isis Development Candidate Checklist</font></div>
        <div>&#160;</div>
        <div style="text-align: justify; font-size: 12pt;"><font style="font-size: 10pt; font-variant: small-caps;"><u>Appendix 5</u></font><font style="font-size: 10pt;"> &#8211; Roche&#8217;s Development/Commercialization Activities and Specific Performance
            Milestone Events</font></div>
        <div>&#160;</div>
        <div style="text-align: justify; font-size: 12pt;"><font style="font-size: 10pt; font-variant: small-caps;"><u>Appendix 6</u></font><font style="font-size: 10pt;"> &#8211; Brain Shuttle Collaboration Patents</font></div>
        <div>&#160;</div>
        <div style="text-align: justify; font-size: 12pt;"><font style="font-size: 10pt; font-variant: small-caps;"><u>Appendix 7</u></font><font style="font-size: 10pt;"> &#8211; Relevant Permitted Licenses as of the Effective Date</font></div>
        <div>&#160;</div>
        <div style="font-size: 12pt;"><u><font style="font-size: 10pt; font-variant: small-caps;">Schedule 1.5.1</font></u><font style="font-size: 10pt; font-variant: small-caps;"> &#8211; </font><font style="font-size: 10pt;">JSC Governance</font></div>
        <div>&#160;</div>
        <div style="font-size: 12pt;"><u><font style="font-size: 10pt; font-variant: small-caps;">Schedule 1.5.3</font></u><font style="font-size: 10pt;"> &#8211; Alliance Management Activities</font></div>
        <div>&#160;</div>
        <div style="font-size: 12pt;"><u><font style="font-size: 10pt; font-variant: small-caps;">Schedule</font><font style="font-size: 10pt;">&#160;1.6.2(b)(i)</font></u><font style="font-size: 10pt;"> &#8211; Cost of ASOs Supplied Under the Brain Shuttle
            Development Candidate-R&amp;D Plan</font></div>
        <div>&#160;</div>
        <div style="font-size: 12pt;"><u><font style="font-size: 10pt; font-variant: small-caps;">Schedule 1.7.1</font></u><font style="font-size: 10pt;"> &#8211; Isis&#8217; Fully Absorbed Cost of Goods Methodology</font></div>
        <div>&#160;</div>
        <div style="font-size: 12pt;"><u><font style="font-size: 10pt; font-variant: small-caps;">Schedule </font><font style="font-size: 10pt;">6.7.2(e)</font></u><font style="font-size: 10pt; font-variant: small-caps;"> &#8211; </font><font style="font-size: 10pt;">Royalty Calculation Examples</font></div>
        <div>&#160;</div>
        <div style="font-size: 12pt;"><u><font style="font-size: 10pt; font-variant: small-caps;">Schedule </font><font style="font-size: 10pt;">6.7.2(f)</font></u><font style="font-size: 10pt;"> &#8211; Allocation of Net Sales</font></div>
        <div>&#160;</div>
        <div style="font-size: 12pt;"><u><font style="font-size: 10pt; font-variant: small-caps;">Schedule</font><font style="font-size: 10pt;">&#160;6.11.1</font></u><font style="font-size: 10pt;"> &#8211; Isis In-License Agreements</font></div>
        <div>&#160;</div>
        <div style="font-size: 12pt;"><u><font style="font-size: 10pt; font-variant: small-caps;">Schedule</font><font style="font-size: 10pt;">&#160;8.2.4(a)</font></u><font style="font-size: 10pt;"> &#8211; Isis Core Technology Patents</font></div>
        <div>&#160;</div>
        <div style="font-size: 12pt;"><u><font style="font-size: 10pt; font-variant: small-caps;">Schedule</font><font style="font-size: 10pt;">&#160;8.2.4(b)</font></u><font style="font-size: 10pt;"> &#8211; Isis Manufacturing and Analytical Patents</font></div>
        <div>&#160;</div>
        <div style="font-size: 12pt;"><u><font style="font-size: 10pt; font-variant: small-caps;">Schedule</font><font style="font-size: 10pt;">&#160;8.2.4(c)</font></u><font style="font-size: 10pt;"> &#8211; Isis Product-Specific Patents</font></div>
        <div>&#160;</div>
        <div style="font-size: 12pt;"><u><font style="font-size: 10pt; font-variant: small-caps;">Schedule</font><font style="font-size: 10pt;">&#160;8.2.7</font></u><font style="font-size: 10pt;"> &#8211; Prior Agreements</font></div>
        <div>&#160;</div>
        <div style="font-size: 12pt;"><u><font style="font-size: 10pt; font-variant: small-caps;">Schedule 8.4.1</font></u><font style="font-size: 10pt;"> &#8211; Roche Existing Brain Shuttle Patents</font></div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">72</font></div>
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        </div>
        <div style="text-align: center; font-variant: small-caps; font-weight: bold;"><u>Appendix 1</u></div>
        <div><br>
        </div>
        <div style="text-align: center; font-weight: bold;">DEFINITIONS</div>
        <div>&#160;</div>
        <div style="text-align: justify;">For purposes of this Agreement, the following capitalized terms will have the following meanings:</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Acceptance</font>&#8221; means, with respect to an NDA, MAA or JNDA filed for a Product, (a) in the United States, the receipt of written notice from the FDA in
          accordance with 21 C.F.R. &#167;314.101(a)(2) that such NDA is officially &#8220;<font style="font-style: italic;">filed</font>,&#8221; (b) in the European Union, receipt of written notice of acceptance by the EMA of such MAA for filing under the centralized
          European procedure in accordance with any feedback received from European Regulatory Authorities; <font style="font-style: italic;">provided that</font> if the centralized filing procedure is not used, then Acceptance will be determined upon the
          acceptance of such MAA by the applicable Regulatory Authority in a Major Market in the EU, and (c) in Japan, receipt of written notice of acceptance of filing of such JNDA from the Koseisho<font style="color: rgb(0, 0, 0);">&#160;</font>(<u>i.e.</u><font style="font-style: italic;">,</font> the Japanese Ministry of Health and Welfare, or any successor agency thereto).</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Additional Core IP</font>&#8221; has the meaning set forth in <u>Section 6.11.3(a)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Additional Costs</font>&#8221; means [***].</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Additional Isis Development Candidate-Cost Estimate</font>&#8221; has the meaning set forth in <u>Section 1.8.3</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Additional Isis In-License Agreements</font>&#8221; has the meaning set forth in <u>Section 6.11.1(b)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Additional Product-Specific Patents</font>&#8221; has the meaning set forth in <u>Section 6.11.2(a)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Affiliate</font>&#8221; of an entity means any corporation, firm, partnership or other entity which directly or indirectly through one or more intermediaries
          controls, is controlled by or is under common control with a Party to this Agreement. An entity will be deemed to control another entity if it (i) owns, directly or indirectly, more than fifty percent (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 entity, or has other comparable ownership interest with respect to any entity other than a
          corporation; or (ii) has the power, whether pursuant to contract, ownership of securities or otherwise, to direct the management and policies of the entity.&#160; Anything to the contrary in this paragraph notwithstanding, Chugai Pharmaceutical Co.,
          Ltd, a Japanese corporation (&#8220;Chugai&#8221;), shall not be deemed an Affiliate of Roche unless Roche provides written notice to Isis of its desire to include Chugai as an Affiliate of Roche.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Agreement</font>&#8221; has the meaning set forth in the Preamble of this Agreement.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Agreement</font>&#160;<font style="font-weight: bold; font-style: italic;">Term</font>&#8221; has the meaning set forth in <u>Section 10.1</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Alliance Manager</font>&#8221; has the meaning set forth in <u>Section 1.5.3</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">ANDA</font>&#8221; means an Abbreviated New Drug Application and all amendments and supplements thereto filed with the FDA, or the equivalent application filed with
          any equivalent agency or governmental authority outside the U.S. (including any supra-national agency such as the EMA in the EU).</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Annual</font>&#8221; means the period covering a Calendar Year or occurring once per Calendar Year, as the context requires.</div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">73</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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;">&#8220;<font style="font-weight: bold; font-style: italic;">API</font>&#8221; means the bulk active pharmaceutical ingredient manufactured in accordance with cGMP for a Product.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Applicable Law</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">Law</font>&#8221; means all applicable laws, statutes, rules, regulations and other
          pronouncements having the effect of law of any federal, national, multinational, state, provincial, county, city or other political subdivision, agency or other body, domestic or foreign, including any applicable rules, regulations, guidelines,
          or other requirements of the Regulatory Authorities that may be in effect from time to time.</div>
        <div>&#160;</div>
        <div style="text-align: justify; color: rgb(0, 0, 0);">&#8220;<font style="font-weight: bold; font-style: italic;">Approval</font>&#8221; means (i) with respect to a Product in the EU, the earlier to occur of (A) approval from the applicable Regulatory
          Authority in at least one member state in the EU sufficient for the manufacture, distribution, use, marketing and sale of such Product, including pricing and reimbursement approval, in such jurisdiction in accordance with Applicable Laws, or (B)
          the First Commercial Sale of a Product in the EU; and (ii) with respect to a Product in any regulatory jurisdiction other than the EU, approval sufficient for the manufacture, distribution, use, marketing and sale of such Product in such
          jurisdiction in accordance with Applicable Laws.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Approved Changes</font>&#8221; means any changes (including number of subjects, duration of dosing, additional studies, additional endpoints, additional analysis,
          etc.) to the Isis Development Candidate-R&amp;D Plan that are agreed to by Roche (including any changes required by a Regulatory Authority).</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">AS ASO</font>&#8221; has the meaning set forth in <u>Section 2.1.1(b)(ii)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">AS Development Candidate</font>&#8221; has the meaning set forth in <u>Section 2.1.1(b)(ii)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">ASO</font>&#8221; means an oligonucleotide compound, or analog, variant, mimic, or mimetic thereof, having a sequence that is at least six bases long and that
          modulates expression or splicing of a gene target via the binding, partially or wholly, of such compound to the RNA of such gene target.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">ASO-Specific Collaboration Patents</font>&#8221; has the meaning set forth in <u>Section 7.1.3(a)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Audit Report</font>&#8221; has the meaning set forth in <u>Section 6.13</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Back-Up Compound</font>&#8221; means a Compound (other than the first Development Candidate) that was used in any monkey tolerability screen performed to identify the
          first Development Candidate.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Bankruptcy Code</font>&#8221; has the meaning set forth in <u>Section 10.2.5(b)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Brain Shuttle</font>&#8221; has the meaning set forth in <u>Section 1.1</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Brain Shuttle Collaboration Patents</font>&#8221; means Patent Rights arising under the Brain Shuttle Development Candidate-R&amp;D Plan after the Effective Date that
          are Controlled by a Party or any of its Affiliates. The Parties will list on <font style="font-variant: small-caps;"><u>Appendix</u></font><u> 6</u> the Brain Shuttle Collaboration Patents, and will update <font style="font-variant: small-caps;"><u>Appendix</u></font><u> 6</u> when additional Brain Shuttle Collaboration Patents arise under the Brain Shuttle Development Candidate-R&amp;D Plan.</div>
        <div>&#160;</div>
        <div style="text-align: justify; font-size: 12pt;"><font style="font-size: 10pt; color: rgb(0, 0, 0);">&#8220;</font><font style="font-size: 10pt; font-weight: bold; font-style: italic; color: rgb(0, 0, 0);">Brain Shuttle Development Candidate</font><font style="font-size: 10pt; color: rgb(0, 0, 0);">&#8221; has the meaning set forth in </font><u><font style="font-size: 10pt;">Section 1.3.1</font></u><font style="font-size: 10pt;">.</font></div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Brain Shuttle Development Candidate-R&amp;D Plan</font>&#8221; means the research and development plan <font style="color: rgb(0, 0, 0);">attached hereto as </font><font style="font-variant: small-caps; color: rgb(0, 0, 0);"><u>Appendix</u></font><font style="color: rgb(0, 0, 0);"><u> 3</u> (as may be amended in accordance with this Agreement) </font>to conduct the Isis R&amp;D Activities and Roche R&amp;D
          Activities designated under such plan focused on the research and development of a Brain Shuttle Development Candidate.</div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">74</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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;">&#8220;<font style="font-weight: bold; font-style: italic;">Brain Shuttle Development Candidate Reverse</font><font style="font-weight: bold;">&#160;</font><font style="font-weight: bold; font-style: italic;">Royalties</font>&#8221;
          has the meaning set forth in <u>Section 6.10.2</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Brain Shuttle Program Cost Estimate</font>&#8221; has the meaning set forth in <u>Section 1.6.2(b)(i)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Brain Shuttle-Specific Collaboration Patents</font>&#8221; has the meaning set forth in <u>Section 7.1.3(a)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Brain Shuttle Technology</font>&#8221; means the Brain Shuttle technology disclosed in the Roche Existing Brain Shuttle Patents listed on <u>Schedule 8.4.1</u> or
          otherwise existing as of the Effective Date as evidenced by Roche&#8217;s written records.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Breaching Party</font>&#8221; means the Party that is believed by the Non-Breaching Party to be in material breach of this Agreement.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Business Day</font>&#8221; means any day other than a Saturday or Sunday on which banking institutions in New York, New York are open for business.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Calendar Quarter</font>&#8221; means a period of three consecutive months ending on the last day of March, June, September, or December, respectively, and will also
          include the period beginning on the Effective Date and ending on the last day of the Calendar Quarter in which the Effective Date falls.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Calendar Year</font>&#8221; means a year beginning on January 1 (or, with respect to 2013, the Effective Date) and ending on December 31.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">CDA</font>&#8221; has the meaning set forth in <u>Section 11.2</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">cGMP</font>&#8221; means current Good Manufacturing Practices as specified in the United States Code of Federal Regulations, ICH Guideline Q7A, or equivalent laws,
          rules, or regulations of an applicable Regulatory Authority at the time of manufacture.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Change of Control</font>&#8221; means, with respect to a Party: (a) the acquisition by any Third Party of beneficial ownership of more than fifty percent (50%) of the
          then outstanding common shares or voting power of such Party, other than acquisitions by employee benefit plans sponsored or maintained by such Party; (b) the consummation of a business combination involving such Party, unless, following such
          business combination, the stockholders of such Party immediately prior to such business combination beneficially own directly or indirectly more than fifty percent (50%) of the then outstanding common shares or voting power of the entity
          resulting from such business combination.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Change Overruns</font>&#8221; has the meaning set forth in <u>Section 1.6.1(b)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">CHDI</font>&#8221; means the CHDI Foundation, Inc.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Claims</font>&#8221; has the meaning set forth in <u>Section 9.1</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Clinical Study</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">Clinical Studies</font>&#8221; means a Phase 1 Trial, Phase 2 Trial,
          Registration-Directed Trial or Phase 4 Trial, or such other study in humans that is conducted in accordance with good clinical practices and is designed to generate data in support or maintenance of an NDA, MAA, JNDA or other similar marketing
          application.</div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">75</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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; color: rgb(0, 0, 0);">&#8220;<font style="font-weight: bold; font-style: italic;">CMO</font>&#8221; means a Third Party contract manufacturer Manufacturing API or finished drug Product for any purpose under this Agreement.</div>
        <div>&#160;</div>
        <div style="text-align: justify; color: rgb(0, 0, 0);">&#8220;<font style="font-weight: bold; font-style: italic;">Collaboration</font>&#8221; means the conduct of research and development of a Compound, Isis Development Candidate, or Brain Shuttle Development
          Candidate (as applicable), in each case in accordance with the applicable R&amp;D Plan.</div>
        <div>&#160;</div>
        <div style="text-align: justify; color: rgb(0, 0, 0);">&#8220;<font style="font-weight: bold; font-style: italic;">Collaboration Patents</font>&#8221; means collectively Roche Collaboration Patents, Isis Collaboration Patents and Jointly-Owned Collaboration
          Patents.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Commercialize</font>,&#8221; &#8220;<font style="font-weight: bold; font-style: italic;">Commercialization</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">Commercializing</font>&#8221;
          means any and all activities directed to marketing, promoting, detailing, distributing, importing, having imported, exporting, having exported, selling or offering to sell a Product following receipt of Approval for a Product in the applicable
          country, including conducting pre-and post-Approval activities, including studies reasonably required to increase the market potential of a Product and studies to provide improved formulation and Product delivery, and launching and promoting a
          Product in each country.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Commercializing Party</font>&#8221; means (a) Roche, with respect to a Product that is being Developed and Commercialized by or on behalf of Roche, its Affiliates or
          Sublicensees hereunder, and (b) Isis, with respect to a Discontinued Product that is being Developed and Commercialized by or on behalf of Isis, its Affiliates or Sublicensees hereunder.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Commercially Reasonable Efforts</font>&#8221; means the carrying out of discovery, research, development or commercialization activities using good-faith commercially
          reasonable and diligent efforts that the applicable Party would reasonably devote to a compound or product of similar market potential or profit potential at a similar stage in development or product life resulting from its own research efforts,
          based on conditions then prevailing and taking into account, without limitation, issues of safety and efficacy, regulatory authority-approved labeling, product profile, the competitiveness of alternative products in the marketplace, the likely
          timing of the product&#8217;s entry into the market, the patent and other proprietary position, the likelihood of approval and other relevant scientific, technical and commercial factors. The Isis Development Candidate-R&amp;D Plan attached to this
          Agreement as of the Effective Date as <font style="font-variant: small-caps;"><u>Appendix</u></font><u> 2</u> exemplifies a level of diligence that meets the Commercially Reasonable Efforts standard required under this Agreement. Without
          limiting any of the foregoing, (A) Commercially Reasonable Efforts as it applies to Roche&#8217;s Development or Commercialization of a Product hereunder includes the use of Commercially Reasonable Efforts to (i) perform the Roche R&amp;D Activities
          designated under the R&amp;D Plans in accordance with the timelines set forth therein, (ii) perform the activities set forth in each IDCP in accordance with the timelines set forth therein, (iii) perform the &#8220;<font style="font-style: italic;">General



            Activities</font>&#8221; set forth in <font style="font-variant: small-caps;"><u>Appendix</u></font><u> 5</u>, and (iv) achieve the specific performance milestone events set forth in <font style="font-variant: small-caps;"><u>Appendix</u></font><u>
            5</u> (&#8220;<font style="font-weight: bold; font-style: italic;">Specific Performance Milestone Events</font>&#8221;) for a Product on the timeline set forth in <font style="font-variant: small-caps;"><u>Appendix</u></font><u> 5</u>; <font style="font-style: italic;">provided, however</font>, if (X) regulatory or Development issues arise that are outside of Roche&#8217;s reasonable control and make achievement of any such Specific Performance Milestone Event on the stated timeline
          impossible, or (Y) an Isis Development Candidate is being Developed but Roche subsequently decides to Develop a Brain Shuttle Development Candidate in lieu of such Isis Development Candidate, the Parties will meet and negotiate in good faith to
          revise, consistent with any applicable Isis In-License Agreements, the date by which the applicable Specific Performance Milestone Event must be achieved; and (B) Commercially Reasonable Efforts as it applies to Isis&#8217; Development of a Product
          hereunder includes use of Commercially Reasonable Efforts to perform the Isis R&amp;D Activities designated under the R&amp;D Plans in accordance with the timelines set forth therein.&#160; However, Roche (and its Affiliates) does not always seek to
          market its own products in every country or seek to obtain regulatory approval in every country or for every potential indication. As a result, the exercise of diligence by Roche is to be determined by judging Roche&#8217;s commercially reasonable
          efforts in the Major Markets, taken as a whole.</div>
        <div style="text-align: justify;"> <br>
        </div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">76</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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;">&#8220;<font style="font-weight: bold; font-style: italic;">Companion Diagnostic IP</font>&#8221; has the meaning set forth in <u>Section 10.4.2(c)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Companion Diagnostic Product</font>&#8221; has the meaning set forth in <u>Section 10.4.2(c)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Competitive Infringement</font>&#8221; has the meaning set forth in <u>Section 7.5.1</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Compound</font>&#8221; means an ASO that is designed to bind to (i) the RNA that encodes HTT (such ASO, a &#8220;<font style="font-weight: bold; font-style: italic;">Non-Allele


            Selective Compound</font>&#8221;); or (ii) a SNP site within an HTT RNA that is associated with an expanded CAG repeat to selectively reduce the expanded CAG-repeat containing RNA relative to the normal HTT RNA via an RNase H dependent mechanism
          (such ASO, an &#8220;<font style="font-weight: bold; font-style: italic;">Allele Selective Compound</font>&#8221;), in each case where such ASO is discovered by Isis prior to or in the performance of an R&amp;D Plan.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Compulsory Sublicense</font>&#8221; means a Sublicense granted to a Third Party, through the order, decree or grant of a governmental authority having competent
          jurisdiction, authorizing such Third Party to manufacture, use, sale, offer for sale, import or export a Product in any country.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Compulsory Sublicensee</font>&#8221; means a Third Party that was granted a Compulsory Sublicense.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Confidential Information</font>&#8221; has the meaning set forth in <u>Section 11.1</u>. &#8220;<font style="font-style: italic;">Confidential Information</font>&#8221; does not
          include information that:</div>
        <div>&#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="z5ddc67dbeb8f40ab8f54d14b549a71df">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>was in the lawful knowledge and possession of the Receiving Party or its Affiliates prior to the time it was disclosed to, or learned by, the Receiving Party or its Affiliates, or was otherwise developed independently by the Receiving
                  Party or its Affiliates, as evidenced by written records kept in the ordinary course of business, or other documentary proof of actual use by the Receiving Party or its Affiliates;</div>
              </td>
            </tr>

        </table>
        <div>&#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="zfaaeb3e8c8af435e899f01d9f62a6141">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>was generally available to the public or otherwise part of the public domain at the time of its disclosure to the Receiving Party or its Affiliates;</div>
              </td>
            </tr>

        </table>
        <div>&#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="ze9c6fc900d1d41c0adbea5689449eef9">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(c)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>became generally available to the public or otherwise part of the public domain after its disclosure and other than through any act or omission of the Receiving Party or its Affiliates in breach of this Agreement; or</div>
              </td>
            </tr>

        </table>
        <div>&#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="zfcb88806ebd74cd28162fa66c2c61a6d">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(d)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>was disclosed to the Receiving Party or its Affiliates, other than under an obligation of confidentiality, by a Third Party who had no obligation to the Disclosing Party or its Affiliates not to disclose such information to others.</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">77</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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;">&#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 possession of the ability to grant a license or sublicense
          hereunder without violating the terms of any agreement with any Third Party; <font style="font-style: italic;">provided, however</font>, that if a Party has a right to grant a license or sublicense, with respect to an item of intellectual
          property to the other Party only upon payment of compensation (including milestones or royalties) to a Third Party (&#8220;<font style="font-weight: bold; font-style: italic;">Third Party Compensation</font>&#8221;) (other than Isis Supported Pass-Through
          Costs in the case of Isis, and other than Roche Supported Pass-Through Costs in the case of Roche), then the first Party will be deemed to have &#8220;<font style="font-style: italic;">Control</font>&#8221; of the relevant item of intellectual property only
          if the other Party agrees to bear the cost of such Third Party Compensation. Notwithstanding anything to the contrary under this Agreement, with respect to any Third Party that becomes an Affiliate of a Party after the Effective Date (including a
          Third Party acquirer), no intellectual property of such Third Party will be included in the licenses granted hereunder by virtue of such Third Party becoming an Affiliate of such Party.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Cover</font>,&#8221; &#8220;<font style="font-weight: bold; font-style: italic;">Covered</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">Covering</font>&#8221;
          means, with respect to a patent, that the act of making, using or selling by an unauthorized Person would infringe a Valid Claim included in such patent, or in the case of a patent that is a patent application, would infringe a Valid Claim in
          such patent application if it were to issue as a patent.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">CREATE Act</font>&#8221; means the Cooperative Research and Technology Enhancement Act of 2004, 35 U.S.C. &#167; 103(c)(2)-(c)(3).</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Develop</font>,&#8221; &#8220;<font style="font-weight: bold; font-style: italic;">Developing</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">Development</font>&#8221;
          means with respect to a Product, any and all discovery, characterization, or preclinical (including IND-Enabling Toxicology Studies), clinical, or regulatory activity with respect to a Product to seek Approval (including the submission of all
          necessary filings with applicable Regulatory Authorities to support such preclinical and clinical activities and Approval), including human clinical trials conducted after Approval of a Product to seek Approval for additional indications for a
          Product.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Development Candidate</font>&#8221; means (i) a Brain Shuttle Development Candidate, or (ii) an Isis Development Candidate.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Development Candidate Data Package</font>&#8221; means, with respect to [***] the [***]; <font style="font-style: italic;">provided</font> such package contains the
          [***]. The checklist Isis uses as of the Effective Date when reviewing potential development candidates for approval is attached hereto as <font style="font-variant: small-caps;"><u>Appendix</u></font><u> 4</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Disclosing Party</font>&#8221; has the meaning set forth in <u>Section 11.1</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Discontinued Product</font>&#8221; means a Product that is the subject of a termination under this Agreement.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Effective Date</font>&#8221; has the meaning set forth in the Preamble of this Agreement.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">EMA</font>&#8221; means the European Medicines Agency and any successor entity thereto.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">European Union</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">EU</font>&#8221; means each and every country or territory that is officially part of
          the European Union.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Executives</font>&#8221; has the meaning set forth in <u><font style="font-weight: normal;">Section 12.1.1</font></u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Existing Diagnostic Agreement</font>&#8221; means that certain Non-Exclusive G-Clamp License Agreement between Isis and F. Hoffmann-La Roche Ltd dated April 26, 2011.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">FDA</font>&#8221; means the United States Food and Drug Administration and any successor entity thereto.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">FDCA</font>&#8221; shall mean the United States Food, Drug and Cosmetics Act.</div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">78</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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;">&#8220;<font style="font-weight: bold; font-style: italic;">Field</font>&#8221; means the prophylactic or therapeutic use or form of administration of a Product for any indication.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">First Commercial Sale</font>&#8221; means the first sale of a Product by Roche, its Affiliate or its Sublicensee to a Third Party in a particular country after
          Approval of a Product has been obtained in such country.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">FTE</font>&#8221; means a total of forty-seven (47) weeks or one thousand eight hundred eighty (1,880) hours per year of work on the Development of a Product carried
          out by employees of a Party having the appropriate relevant expertise to conduct such activities.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">FTE Rate</font>&#8221; means [***]. The FTE Rate will be prorated for the actual portion of the full year the employee works under this Agreement. The FTE Rate will
          be increased each Calendar Year after 2013 by the [***].</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Full Royalty Period</font>&#8221; has the meaning set forth in <u>Section 6.7.2(a)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Fully Absorbed Cost of Goods</font>&#8221; means the costs incurred by Isis as determined using the methodology set forth in <u><font style="font-variant: small-caps;">Schedule 1.7.1</font></u> fairly applied and as employed on a consistent basis throughout Isis&#8217; operations<font style="font-variant: small-caps;">.</font></div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Generic Product</font>&#8221;<font style="font-weight: bold;">&#160;</font>means the product(s) of one or more Third Party that is not a Sublicensee, which has the same
          active pharmaceutical ingredient as a Product and for which in the U.S. an ANDA has been filed naming such Product as the reference listed drug or outside of the U.S., an equivalent process where bioequivalence to such Product has been asserted.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Group Sublicensee</font>&#8221; means any individual, corporation, association or other business entity:</div>
        <div>&#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="zd0464a939e3b40fa8a2d062c2a6d2822">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(i)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>to which Roche has granted a Sublicense;</div>
              </td>
            </tr>

        </table>
        <div>&#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="z4c5da8875596403b85930ce4ff51a869">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(ii)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>that is not an Affiliate of Roche; and</div>
              </td>
            </tr>

        </table>
        <div>&#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="z1caed8d0b3274967bed8c6dc1e365775">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(iii)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>that is consolidated within Roche&#8217;s externally published audited financial statements.</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">HSR Act</font>&#8221; means Section 7A of the Clayton Act, as added by Title II of the Hart-Scott-Rodino Antitrust Improvement Act of 1976, as amended, and the rules
          and regulations promulgated thereunder.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Huntingtin</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">HTT</font>&#8221; means the human gene known as IT15 or HD (GenBank accession
          #NM_002111.5), or any alternative splice variants, mutants, polymorphisms and fragments thereof.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Huntington&#8217;s Disease</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">HD</font>&#8221; means the hereditary disorder caused by mutation associated
          with trinucleotide repeat expansion in the Huntingtin gene on chromosome 4p.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">IDCP</font>&#8221; has the meaning set forth in <u>Section 5.1</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">IND</font>&#8221; means an Investigational New Drug Application (as defined in the Food, Drug and Cosmetic Act, as amended) filed with the FDA or its foreign
          counterparts.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">IND-Enabling Toxicology Studies</font>&#8221; means the pre-clinical studies required to file an IND.</div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">79</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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;">&#8220;<font style="font-weight: bold; font-style: italic;">Indemnitee</font>&#8221; has the meaning set forth in <u>Section 9.3</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Independent Expert</font>&#8221; has the meaning set forth <u>Section 5.1.1</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Initiation</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">Initiate</font>&#8221; means, (i) with respect to any IND-Enabling Toxicology Study,
          dosing of the first animal subject in such IND-Enabling Toxicology Study, (ii) with respect to any Clinical Study performed by Roche, its Affiliates or Sublicensees, the date the first patient is dosed with a Product in such Clinical Study, and
          (iii) with respect to any Clinical Study performed by Isis, its Affiliates or Sublicensees (excluding Roche), the date the first clinical trial site is approved by the applicable Reviewing Entity to participate in such Clinical Study.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Isis</font>&#8221; has the meaning set forth in the Preamble of this Agreement.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Isis Collaboration Know-How</font>&#8221; means Know-How discovered, developed, invented or created solely by or on behalf of Isis or its Affiliate or a Third Party
          acting on their behalf in the performance of an R&amp;D Plan, that is necessary or useful to Develop, Manufacture or Commercialize a Product in the Field.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Isis Collaboration Patents</font>&#8221; means Patent Rights discovered, developed, invented or created solely by or on behalf of Isis or its Affiliate or a Third
          Party acting on their behalf in the performance of an R&amp;D Plan, that are necessary or useful to Develop, Manufacture or Commercialize a Product in the Field.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Isis Core Brain Shuttle Collaboration Patent</font>&#8221; has the meaning set forth in <u>Section 7.2.2(a)(i)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Isis Core Technology Patents</font>&#8221; means all Patent Rights owned, used, developed by, or licensed to Isis or its Affiliates, in each case to the extent
          Controlled by Isis or its Affiliates on the Effective Date or at any time during the Agreement Term, claiming subject matter generally applicable to ASOs, other than Isis Product-Specific Patents or Isis Manufacturing and Analytical Patents. <font style="color: rgb(0, 0, 0);">A list of </font>Isis Core Technology Patents <font style="color: rgb(0, 0, 0);">as of the </font>Effective Date <font style="color: rgb(0, 0, 0);">is set forth on </font><u><font style="font-variant: small-caps; color: rgb(0, 0, 0);">Schedule</font><font style="color: rgb(0, 0, 0);">&#160;</font>8.2.4<font style="color: rgb(0, 0, 0);">(a)</font></u><font style="color: rgb(0, 0, 0);"> attached hereto.</font></div>
        <div>&#160;</div>
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            Isis&#8217; RMC in accordance with Isis&#8217; standard procedures for designating development candidates (and giving good faith consideration to the input of Roche&#8217;s representatives on the JSC) as ready to start IND-Enabling Toxicology Studies. The
            checklist Isis uses as of the Effective Date when reviewing potential development candidates for approval is attached hereto as <font style="font-variant: small-caps;"><u>Appendix 4</u></font>. The first Isis Development Candidate to be
            designated a Development Candidate hereunder is referred to throughout this Agreement as the &#8220;<font style="font-style: italic;">first</font>&#8221; Isis Development Candidate. Any work on one or more additional or replacement Isis Development
            Candidates may be performed under an amended Isis Development Candidate-R&amp;D Plan as contemplated by <u>Section 1.8</u>.&#160; </font></div>
        <div>&#160;</div>
        <div style="text-align: justify; color: rgb(0, 0, 0);">&#8220;<font style="font-weight: bold; font-style: italic;">Isis Development Candidate-R&amp;D Plan</font>&#8221; means the research and development plan attached hereto as <font style="font-variant: small-caps;"><u>Appendix</u></font><u> 2</u> (as may be amended in accordance with this Agreement) to conduct the Isis R&amp;D Activities and Roche R&amp;D Activities designated under such plan focused on the research and development of an Isis
          Development Candidate.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Isis Development Candidate Reverse</font><font style="font-weight: bold;">&#160;</font><font style="font-weight: bold; font-style: italic;">Royalties</font>&#8221; has the
          meaning set forth in <u>Section 6.10.1</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Isis In-License Agreements</font>&#8221; has the meaning set forth in <u>Section 6.11.1(a)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Isis Internal ASO Safety Database</font>&#8221; has the meaning set forth in <u>Section 5.2.2(a)</u>.</div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">80</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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;">&#8220;<font style="font-weight: bold; font-style: italic;">Isis Know-How</font>&#8221; means any Know-How, including Isis&#8217; interest in any Jointly-Owned Collaboration Know-How, owned, used, developed by, or licensed to Isis
          or its Affiliates, in each case to the extent Controlled by Isis or its Affiliates on the Effective Date or at any time during the Agreement Term. Isis Know-How does not include the Isis Manufacturing and Analytical Know-How.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Isis Manufacturing and Analytical Know-How</font>&#8221; means Know-How, including Isis&#8217; interest in any Jointly-Owned Collaboration Know-How, that relates to the
          synthesis or analysis of a Product regardless of sequence or chemical modification, owned, used, developed by, or licensed to Isis or its Affiliates, in each case to the extent Controlled by Isis or its Affiliates on the Effective Date or at any
          time during the Agreement Term. Isis Manufacturing and Analytical Know-How does not include the Isis Know-How.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Isis Manufacturing and Analytical Patents</font>&#8221; means Patent Rights, including Isis&#8217; interest in any Jointly-Owned Collaboration Patents, that claim methods
          and materials used in the synthesis or analysis of a Product regardless of sequence or chemical modification, owned, used, developed by, or licensed to Isis or its Affiliates, in each case to the extent Controlled by Isis or its Affiliates on the
          Effective Date or at any time during the Agreement Term. A list of Isis Manufacturing and Analytical Patents as of the Effective Date is set forth on <font style="font-variant: small-caps;"><u>Schedule</u></font><u> 8.2.4(b)</u> attached hereto.
          Isis Manufacturing and Analytical Patents do not include the Isis Product-Specific Patents or the Isis Core Technology Patents.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Isis Product-Specific Brain Shuttle Collaboration Patent</font>&#8221; has the meaning set forth in <u>Section 7.2.2(a)(ii)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Isis Product-Specific Patents</font>&#8221; means Patent Rights Controlled by Isis or any of its Affiliates on or after the Effective Date claiming (i) the specific
          composition of matter of an Isis Development Candidate; (ii) methods of using an Isis Development Candidate as a prophylactic or therapeutic; or (iii) the specific mechanism of action of an Isis Development Candidate, in each case to the extent
          necessary to Develop, Manufacture or Commercialize an Isis Development Candidate; <font style="font-style: italic;">provided however</font>, Patent Rights Controlled by Isis or any of its Affiliates that (y) include claims that are directed to
          subject matter applicable to ASOs in general, or (z) include an ASO, the sequence of which targets both (a) the RNA that encodes HTT and (b) ASOs that do not target the RNA encoding HTT, will not be considered Isis Product-Specific Patents, and
          in the case of (y) and (z), such Patent Rights will be considered Isis Core Technology Patents. A list of Isis Product-Specific Patents as of the Effective Date is set forth on <font style="font-variant: small-caps;"><u>Schedule</u></font><u>
            8.2.4(c)</u> attached hereto.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Isis R&amp;D Activities</font>&#8221; means the research, pre-clinical and/or clinical activities for which Isis is designated as responsible under an R&amp;D Plan.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Isis Supported Pass-Through Costs</font>&#8221; means the licensing costs and payments payable by Isis to Third Parties to the extent arising from a Third Party
          agreement under [***].</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Japan NDA</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">JNDA</font>&#8221; means<font style="color: rgb(0, 0, 0);"> the Japanese equivalent of an </font>NDA


          <font style="color: rgb(0, 0, 0);">filed with the </font>Koseisho (<u>i.e.</u><font style="font-style: italic;">,</font> the Japanese Ministry of Health and Welfare, or any successor agency thereto)<font style="color: rgb(0, 0, 0);">.</font></div>
        <div>&#160;</div>
        <div style="text-align: justify; font-size: 12pt;"><font style="font-size: 10pt; color: rgb(0, 0, 0);">&#8220;</font><font style="font-size: 10pt; font-weight: bold; font-style: italic;">JNDA Approval</font><font style="font-size: 10pt; color: rgb(0, 0, 0);">&#8221; means the </font><font style="font-size: 10pt;">Approval <font style="color: rgb(0, 0, 0);">of a </font>JNDA <font style="color: rgb(0, 0, 0);">by the </font>Koseisho<font style="color: rgb(0, 0, 0);">&#160;</font>(<u>i.e.</u><font style="font-style: italic;">,</font> the Japanese Ministry of Health and Welfare, or any successor agency thereto) <font style="color: rgb(0, 0, 0);">for the applicable </font>Product <font style="color: rgb(0, 0, 0);">in Japan.</font></font></div>
        <div>&#160;</div>
        <div style="text-align: justify; font-size: 12pt;"><font style="font-size: 10pt; color: rgb(0, 0, 0);">&#8220;</font><font style="font-size: 10pt; font-weight: bold; font-style: italic;">Joint Patent Committee</font><font style="font-size: 10pt; color: rgb(0, 0, 0);">&#8221; or &#8220;</font><font style="font-size: 10pt; font-weight: bold; font-style: italic;">JPC</font><font style="font-size: 10pt;">&#8221; has the meaning set forth in <u>Section 7.1.3(a)</u>.</font></div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">81</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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;">&#8220;<font style="font-weight: bold; font-style: italic;">Jointly-Owned Collaboration Know-How</font>&#8221; means Know-How discovered, developed, invented or created jointly in the performance of an R&amp;D Plan by or on
          behalf of both Parties or their respective Affiliates or Third Parties acting on their behalf that is necessary or useful to Develop, Manufacture or Commercialize a Product in the Field.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Jointly-Owned Collaboration Patents</font>&#8221; means any Patent Rights discovered, developed, invented or created jointly in the performance of an R&amp;D Plan by
          or on behalf of both Parties or their respective Affiliates or Third Parties acting on their behalf that is necessary or useful to Develop, Manufacture or Commercialize a Product in the Field.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Jointly-Owned Collaboration Technology</font>&#8221; means Jointly-Owned Collaboration Know-How and Jointly-Owned Collaboration Patents.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">JSC</font>&#8221; has the meaning set forth in <u>Section 1.5.1</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Know-How</font>&#8221; means unpatented inventions, technical information, know-how and materials, including technology, data, compositions, formulas, biological
          materials, assays, reagents, constructs, compounds, discoveries, procedures, processes, practices, protocols, methods, techniques, results of experimentation or testing, knowledge, trade secrets, skill and experience.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Lead Party</font>&#8221; has the meaning set forth in <u>Section 7.4.1</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Licensed CMO</font>&#8221; has the meaning set forth in <u>Section 4.1.4(a)(ii)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Licensed Know-How</font>&#8221; means Isis Manufacturing and Analytical Know-How, Isis Know-How, Isis Collaboration Know-How, and Isis&#8217; interest in any Jointly-Owned
          Collaboration Know-How. For clarity, Licensed Know-How does not include any Know-How covering formulation technology or delivery devices <font style="font-style: italic;"><u>unless</u></font> such Know-How is included in any Isis Collaboration
          Know-How or Jointly-Owned Collaboration Know-How.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Licensed Patents</font>&#8221; means the Isis Product-Specific Patents, Isis Core Technology Patents, Isis Manufacturing and Analytical Patents, Isis Collaboration
          Patents, and Isis&#8217; interest in any Jointly-Owned Collaboration Patents and Brain Shuttle Collaboration Patents. For clarity, Licensed Patents do not include any Patent Rights claiming formulation technology or delivery devices <font style="font-style: italic;"><u>unless</u></font> such Patent Rights are included in any Isis Collaboration Patents or Jointly-Owned Collaboration Patents.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Licensed Technology</font>&#8221; means any and all Licensed Patents and Licensed Know-How, in each case to the extent necessary or useful to Develop, Manufacture or
          Commercialize a Product. &#8220;<font style="font-style: italic;">Licensed Technology</font>&#8221; expressly excludes all technology licensed to Isis under the UTSW Agreement because such technology is not utilized by, nor does it cover, the Compounds.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Linker-Specific Collaboration Patents</font>&#8221; has the meaning set forth in <u>Section 7.1.3(a)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Losses</font>&#8221; has the meaning set forth in <u>Section 9.1</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify; font-size: 12pt;"><font style="font-size: 10pt; color: rgb(0, 0, 0);">&#8220;</font><font style="font-size: 10pt; font-weight: bold; font-style: italic;">MAA</font><font style="font-size: 10pt; color: rgb(0, 0, 0);">&#8221;
            means a marketing authorization application filed with the </font><font style="font-size: 10pt;">EMA <font style="color: rgb(0, 0, 0);">after completion of </font>Clinical Studies <font style="color: rgb(0, 0, 0);">to obtain </font>Approval



            <font style="color: rgb(0, 0, 0);">for a </font>Product <font style="color: rgb(0, 0, 0);">under the centralized European filing procedure or, if the centralized </font>EMA <font style="color: rgb(0, 0, 0);">filing procedure is not used,
              filed using the applicable procedures in any </font>European Union <font style="color: rgb(0, 0, 0);">country.</font></font></div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">MAA Approval</font>&#8221; means the Approval <font style="color: rgb(0, 0, 0);">of an </font>MAA <font style="color: rgb(0, 0, 0);">by the </font>EMA <font style="color: rgb(0, 0, 0);">for a </font>Product <font style="color: rgb(0, 0, 0);">in any country in the </font>EU.</div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">82</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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; font-size: 12pt;"><font style="font-size: 10pt; color: rgb(0, 0, 0);">&#8220;</font><font style="font-size: 10pt; font-weight: bold; font-style: italic;">Major Market</font><font style="font-size: 10pt; color: rgb(0, 0, 0);">&#8221; means any of the following countries: the United States, Japan, the </font><font style="font-size: 10pt;">United Kingdom<font style="color: rgb(0, 0, 0);">, </font>Germany<font style="color: rgb(0, 0, 0);">, </font>France<font style="color: rgb(0, 0, 0);">, </font>Italy, Spain, Brazil, Russia, India and China<font style="color: rgb(0, 0, 0);">.</font></font></div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Manufacture</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">Manufactured</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">Manufacturing</font>&#8221;
          means any activity involved in or relating to the manufacturing, quality control testing (including in-process, release and stability testing), releasing or packaging, for pre-clinical and clinical purposes, of API or a Product in finished form.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Milestone Event</font>&#8221; means a Pre-Licensing Milestone Event or a Post-Licensing Milestone Event, as the case may be.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Minimum Third Party Payments</font>&#8221; means [***].</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">NAS Development Candidate</font>&#8221; has the meaning set forth in <u>Section 2.1.1(b)(i)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify; font-size: 12pt;"><font style="font-size: 10pt; color: rgb(0, 0, 0);">&#8220;</font><font style="font-size: 10pt; font-weight: bold; font-style: italic;">NDA</font><font style="font-size: 10pt; color: rgb(0, 0, 0);">&#8221;</font><font style="font-size: 10pt; font-weight: bold; color: rgb(0, 0, 0);">&#160;</font><font style="font-size: 10pt; color: rgb(0, 0, 0);">means a </font><font style="font-size: 10pt;">New Drug Application <font style="color: rgb(0, 0, 0);">filed with the
            </font>FDA <font style="color: rgb(0, 0, 0);">after completion of </font>Clinical Studies <font style="color: rgb(0, 0, 0);">to obtain </font>Approval <font style="color: rgb(0, 0, 0);">for a Product</font>&#160;<font style="color: rgb(0, 0, 0);">in the United States.</font></font></div>
        <div>&#160;</div>
        <div style="text-align: justify; font-size: 12pt;"><font style="font-size: 10pt; color: rgb(0, 0, 0);">&#8220;</font><font style="font-size: 10pt; font-weight: bold; font-style: italic;">NDA Approval</font><font style="font-size: 10pt; color: rgb(0, 0, 0);">&#8221; means the </font><font style="font-size: 10pt;">Approval <font style="color: rgb(0, 0, 0);">of an </font>NDA <font style="color: rgb(0, 0, 0);">by the </font>FDA <font style="color: rgb(0, 0, 0);">for a Product</font>&#160;<font style="color: rgb(0, 0, 0);">in the U.S.</font></font></div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Net Sales</font>&#8221; of a Product in a particular period will mean the amount calculated by subtracting from the Sales of such Product for such period: (A) a lump
          sum deduction of four percent (4%) of Sales under item (i) of the &#8220;<font style="font-style: italic;">Sales</font>&#8221; definition in lieu of those deductions that are not accounted for on a Product-by-Product basis (<u>e.g.</u>, freight, postage
          charges, transportation insurance, packing materials for dispatch of goods, custom duties); (B) uncollectible amounts accrued during such period based on a proportional allocation of the total bad debts accrued during such period; (C) credit card
          charges (including processing fees) accrued during such period on such Sales; and (D) government mandated fees and taxes and other government charges accrued during such period for such Product including, for example, any fees, taxes or other
          charges that become due in connection with any healthcare reform, change in government pricing or discounting schemes, or other action of a government or regulatory body; provided that the foregoing deductions under (A) to (D) were not already
          taken as a gross-to-net deduction in accordance with the then currently used International Financial Reporting Standards (IFRS) in the calculation of Sales of such Product for such period.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">New Third Party Licenses</font>&#8221; has the meaning set forth in <u>Section 8.3.2</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Non-Breaching Party</font>&#8221; means the Party that believes the Breaching Party is in material breach of this Agreement.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">[***]</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Omnibus Collaboration Patents</font>&#8221; has the meaning set forth in <u>Section 7.1.3(a)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Option</font>&#8221; has the meaning set forth in <u>Section 3.1</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Option Deadline</font>&#8221; has the meaning set forth in <u>Section 3.1</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Option Period</font>&#8221; has the meaning set forth in <u>Section 1.1</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Party</font>&#8221; or &#8220;<font style="font-weight: bold; font-style: italic;">Parties</font>&#8221; means Roche and Isis individually or collectively.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Patent Costs</font>&#8221; means the reasonable fees and expenses paid to outside legal counsel, and filing, maintenance and other reasonable out-of-pocket expenses
          paid to Third Parties, incurred in connection with the Prosecution and Maintenance of Patent Rights.</div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">83</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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;">&#8220;<font style="font-weight: bold; font-style: italic;">Patent Rights</font>&#8221; means (a) patents, patent applications and similar government-issued rights protecting inventions in any country or jurisdiction however
          denominated, (b) all priority applications, divisionals, continuations, substitutions, 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 registrations, reissues, renewals, re-examinations, confirmations, supplementary protection certificates, and extensions of any of (a), (b) or (c).</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Permitted Licenses</font>&#8221; means (1) licenses granted by Isis before or after the Effective Date to any Third Party under the Isis Core Technology Patents, the
          Isis Manufacturing and Analytical Patents, or the Isis Manufacturing and Analytical Know-How (but not under the Isis Product-Specific Patents) to (a) use oligonucleotides (or supply oligonucleotides to end users) solely to conduct pre-clinical
          research, or (b) enable such Third Party to manufacture or formulate oligonucleotides, where Isis does not assist such Third Party to identify, discover or make a Compound or Product; and (2) material transfer agreements with academic
          collaborators or non-profit institutions solely to conduct noncommercial research. A list of relevant Permitted Licenses as of the Effective Date is set forth on <font style="font-variant: small-caps;"><u>Appendix 7</u></font> attached hereto.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Person</font>&#8221; will mean any corporation, limited or general partnership, limited liability company, joint venture, trust, unincorporated association,
          governmental body, authority, bureau or agency, any other entity or body, or an individual.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Phase 1 Trial</font>&#8221; means the initial clinical testing of a Product in humans (first-in-humans study) in any country that is designed to satisfy the
          requirements of 21 C.F.R. &#167; 312.21(a) FDCA, as amended from time to time, or a foreign equivalent thereof.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Phase 1 Trial Data Package</font>&#8221; means the listing and tables of safety data (and early efficacy data if applicable) available to the Party conducting such
          Phase 1 Trial after the last patient receives his/her last dose of a Product in such Phase 1 Trial.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Phase 2 Trial</font>&#8221; means a human clinical study that is intended to explore a variety of dose and dose response to generate initial evidence of clinical
          safety and activity in a target patient population for which the primary endpoints include a determination of dose ranges and/or a preliminary determination of efficacy in patients being studied as described in 21 C.F.R. &#167; 312.21(b) FDCA, as
          amended from time to time, or a foreign equivalent thereof.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Phase 2 Trial Data Package</font>&#8221; means, with respect to a given Phase 2 Trial, the listing and tables of safety and efficacy data available to Roche after the
          last patient has received his/her last dose of a Product in such Phase 2 Trial.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Phase 4 Trial</font>&#8221; means (i) any Clinical Study conducted to satisfy a requirement of a Regulatory Authority in order to maintain Approval, or (ii) any
          Clinical Study conducted after the first Approval in the same disease state for which a Product received Approval other than for purposes of obtaining Approval.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Post-Licensing Milestone Event</font>&#8221; has the meaning set forth in <u>Section 6.4</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Pre-Clinical Studies</font>&#8221; means <font style="font-style: italic;">in vitro</font> and <font style="font-style: italic;">in vivo</font> studies of a
          Product, not in humans, including those studies conducted in whole animals and other test systems, designed to determine the toxicity, bioavailability, and pharmacokinetics of a Product and whether a Product has a desired effect.</div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">84</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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;">&#8220;<font style="font-weight: bold; font-style: italic;">Pre-Licensing Milestone Event</font>&#8221; has the meaning set forth in <u>Section 6.2</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Prior Agreements</font>&#8221; means the agreements listed on <u><font style="font-variant: small-caps; color: rgb(0, 0, 0);">Schedule </font><font style="font-variant: small-caps;">8.2.7</font></u> attached hereto.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Proceeding</font>&#8221; means an action, suit or proceeding.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Product</font>&#8221; means a finished drug product containing as an active pharmaceutical ingredient (i) an Isis Development Candidate, or (ii) a Brain Shuttle
          Development Candidate.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#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; means, with regard to a Patent
          Right, the preparing, filing, prosecuting and maintenance of such Patent Right, as well as handling re-examinations, reissues, and requests for patent term extensions with respect to such Patent Right, together with the conduct of interferences,
          the defense of oppositions and other similar proceedings with respect to the particular Patent Right. 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; will not include any other enforcement actions taken with respect to a Patent Right.</div>
        <div>&#160;</div>
        <div style="text-align: justify; color: rgb(0, 0, 0);">&#8220;<font style="font-weight: bold; font-style: italic;">R&amp;D Plan</font>&#8221; means either (i) the Isis Development Candidate-R&amp;D Plan, or (ii) the Brain Shuttle Development Candidate-R&amp;D
          Plan.</div>
        <div>&#160;</div>
        <div style="text-align: justify; font-size: 12pt;"><font style="font-size: 10pt; color: rgb(0, 0, 0);">&#8220;</font><font style="font-size: 10pt; font-weight: bold; font-style: italic;">Receiving Party</font><font style="font-size: 10pt;">&#8221; has the
            meaning set forth in <u>Section 11.1</u>.</font></div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Reduced Royalty Period</font>&#8221; has the meaning set forth in <u>Section 6.7.2(d)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Reference Rate</font>&#8221; has the meaning set forth in <u>Section 6.7.2(b)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Registration-Directed Trial</font>&#8221; means a pivotal Clinical Study (whether or not called a &#8220;<font style="font-style: italic;">Phase 3</font>&#8221; Clinical Study)
          [***] intended to establish that a Product is safe and effective for its intended use; and is intended to support NDA filing (or foreign equivalent filing) of such Product in patients having the disease or condition being studied, as described in
          21 C.F.R. &#167; 312.21(c) FDCA, as amended from time to time, or a foreign equivalent thereof.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Registration-Directed Trial Data Package</font>&#8221; means, with respect to a given Registration-Directed Trial, the listing and tables of safety and efficacy data
          available [***].</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Regulatory Authority</font>&#8221; means any governmental authority, including the FDA, EMA or Koseisho (<u>i.e.</u><font style="font-style: italic;">,</font> the
          Japanese Ministry of Health and Welfare, or any successor agency thereto), that has responsibility for granting any licenses or approvals or granting pricing or reimbursement approvals necessary for the marketing and sale of a Product in any
          country.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Reviewing Entity</font>&#8221; means an institutional review board (IRB), research ethics board (REB), European ethical committee (EEC), or equivalent appropriate
          governmental ethical reviewing entity responsible for approving an entity to participate in a Clinical Study as a clinical site.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">RMC</font>&#8221; means Isis&#8217; Research Management Committee, or any successor committee.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Roche</font>&#8221; has the meaning set forth in the Preamble of this Agreement.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Roche Collaboration Know-How</font>&#8221; means Know-How discovered, developed, invented or created solely by or on behalf of Roche or its Affiliate or a Third Party
          acting on their behalf in the performance of an R&amp;D Plan, that is necessary or useful to Develop, Manufacture or Commercialize a Product in the Field.</div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">85</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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;">&#8220;<font style="font-weight: bold; font-style: italic;">Roche Collaboration Patents</font>&#8221; means Patent Rights discovered, developed, invented or created solely by or on behalf of Roche or its Affiliate or a Third
          Party acting on their behalf in the performance of an R&amp;D Plan, that are necessary or useful to Develop, Manufacture or Commercialize a Product in the Field.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Roche Collaboration Technology</font>&#8221; means Roche Collaboration Know-How, Roche Collaboration Patents and Roche&#8217;s interest in any Jointly-Owned Collaboration
          Technology and Brain Shuttle Collaboration Patents.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Roche Existing Brain Shuttle Patents</font>&#8221; has the meaning set forth in <u>Section 8.4.1</u>. A list of Roche Existing Brain Shuttle Patents as of the
          Effective Date is set forth on <u><font style="font-variant: small-caps;">Schedule 8.4.1</font></u> attached hereto.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Roche Full Royalty</font>&#8221; has the meaning set forth in <u>Section 6.7.1</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Roche Know-How</font>&#8221; means any Know-How that (i) did not arise in connection with the performance of an R&amp;D Plan, (ii) is owned, used, developed by, or
          licensed to Roche or its Affiliates, and (iii) is necessary or useful to Develop, Manufacture or Commercialize a Product in the Field, in each case to the extent Controlled by Roche or its Affiliates on the Effective Date or at any time during
          the Agreement Term.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Roche Patents</font>&#8221; means any Patent Rights that (i) did not arise in connection with the performance of an R&amp;D Plan, (ii) are owned, used, developed by,
          or licensed to Roche or its Affiliates, and (iii) are necessary or useful to Develop, Manufacture or Commercialize a Product in the Field, in each case to the extent Controlled by Roche or its Affiliates on the Effective Date or at any time
          during the Agreement Term.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Roche-Prosecuted Patents</font>&#8221; has the meaning set forth in <u>Section 7.2.4</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Roche Reduced Royalty</font>&#8221; has the meaning set forth in <u>Section 6.7.2(b)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Roche R&amp;D Activities</font>&#8221; means the research, pre-clinical and/or clinical activities for which Roche is designated as responsible under an R&amp;D Plan.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Roche Supported Pass-Through Costs</font>&#8221; means the [***].</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Roche-Selected Brain Shuttle Development Candidate</font>&#8221; means that as between a given Isis Development Candidate and a given Brain Shuttle Development
          Candidate, in accordance with <u>Section 5.1.1</u>, the Independent Expert did not recommend that such Brain Shuttle Development Candidate be progressed into Phase 2 Trials.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Roche Technology</font>&#8221; means Roche&#8217;s interest in Roche Collaboration Technology, Roche Know-How, Roche Patents and any trademarks described in <u>Section
            4.1.7</u>, owned, used, developed by, or licensed to Roche or its Affiliates that is necessary or useful to Develop, Manufacture or Commercialize a Product.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Royalty Quotient</font>&#8221; has the meaning set forth in <u>Section 6.7.2(b)</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Sales</font>&#8221; of a Product in a particular period will mean the sum of (i) and (ii):</div>
        <div>&#160;</div>
        <div style="text-align: justify; margin-left: 36pt; font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;">(i)</font><font style="font-size: 10pt;"> the amount stated in Roche sales line of its externally published audited financial
            statements with respect to such Product for such period (excluding sales to any Sublicensee that are used for research or Development or re-sold by such Sublicensee as sales under item (ii) below). This amount reflects the gross invoice price
            at which such Product was sold or otherwise disposed of (other than for use as clinical supplies or free samples) by Roche/Genentech, its Affiliates and Group Sublicensees to Third Parties (excluding sales to any Sublicensee that are used for
            research or Development or re-sold by such Sublicensee as sales under item (ii) below) in such period reduced by gross-to-net deductions, if not previously deducted from such invoiced amount, taken in accordance with the then currently used
            International Financial Reporting Standards (IFRS).</font></div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">86</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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; margin-left: 36pt;">By way of example, the gross-to-net deductions taken in accordance with International Financial Reporting Standards (IFRS) as of the Effective Date include the following:</div>
        <div>&#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="z2e470dddbbd647a4bb6d4c3da9499eb0">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>credits, reserves or allowances granted for (w) damaged, outdated, returned, rejected, withdrawn or recalled Product, (x) wastage replacement and short-shipments, (y) billing errors and (z) indigent patient and similar programs (<u>e.g.</u>,
                  price capitation);</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div>
          <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z7ff6d386f8864ecbada042f77d0e009d" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

              <tr style="vertical-align: top;">
                <td style="width: 72pt;">&#160;</td>
                <td style="vertical-align: top; width: 36pt;">
                  <div style="text-align: justify;">(b)</div>
                </td>
                <td style="vertical-align: top; width: auto;">
                  <div style="text-align: justify;">governmental price reductions and government mandated rebates;</div>
                </td>
              </tr>

          </table>
        </div>
        <div>&#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="z3c535b2f834e4c42b64d778bb20b9114">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top;">(c)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>chargebacks, including those granted to wholesalers, buying groups and retailers;</div>
              </td>
            </tr>

        </table>
        <div>&#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="zc3cb747088744e86a9ae8a55c44ba6d0">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top;">(d)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>customer rebates, including cash sales incentives for prompt payment, cash and volume discounts; and</div>
              </td>
            </tr>

        </table>
        <div>&#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="z4669c1baaafc4b4c8571d0fb1348ced6">

            <tr>
              <td style="width: 72pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top;">(e)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>taxes, duties and any other governmental charges or levies imposed upon or measured by the import, export, use, manufacture or sale of a Product (excluding income or franchise taxes).</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="text-align: justify; margin-left: 36pt;">For the purpose of clarity, sales by Roche/Genentech and its Affiliates to any Sublicensee and/or Group Sublicensee that are used for research or Development or re-sold by such Sublicensee or
          Group Sublicensee as sales under item (ii) below will be excluded from &#8220;<font style="font-style: italic;">Sales</font>&#8221; calculated under this item (i).</div>
        <div>&#160;</div>
        <div style="text-align: justify; margin-left: 36pt; font-size: 12pt;"><font style="font-size: 10pt; font-weight: bold;">(ii)</font><font style="font-size: 10pt;"> Sublicensee (excluding Compulsory Sublicensee) sales amounts reported to Roche and
            its Affiliates in accordance with Sublicensee contractual terms and their then currently used accounting standards. For the purpose of clarity, any Sublicensee sales as reported to Roche in accordance with Compulsory Sublicense agreements will
            be excluded from the Sales amount.</font></div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">SNP</font>&#8221; means single nucleotide polymorphism.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Specific Performance Milestone Event</font>&#8221; has the meaning set forth in the definition of &#8220;<font style="font-style: italic;">Commercially Reasonable Efforts</font>.&#8221;</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Step-In Party</font>&#8221; has the meaning set forth in <u>Section 7.4.1</u>.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Sublicensee</font>&#8221; means a Third Party to whom a Party or its Affiliates or Sublicensees has granted a sublicense or license under any Licensed Technology or
          Roche Technology, as the case may be, licensed to such Party in accordance with the terms of this Agreement.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Third Party</font>&#8221; means a Person or entity other than the Parties or their respective Affiliates.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Third Party Obligations</font>&#8221; means any financial and non-financial encumbrances, obligations, restrictions, or limitations imposed by an agreement between
          Isis and a Third Party (including the Isis In-License Agreements) that relate to a Product, HTT, including field or territory restrictions, covenants, milestone payments, diligence obligations, sublicense revenue, royalties, or other payments.</div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">87</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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;">&#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 fifty states of the United States of America and all of
          its territories and possessions and the District of Columbia.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">UTSW Agreement</font>&#8221; means that certain Exclusive Patent License Agreement between Isis and the University of Texas Southwestern Medical Center at Dallas
          dated June 24, 2010.</div>
        <div>&#160;</div>
        <div style="text-align: justify;">&#8220;<font style="font-weight: bold; font-style: italic;">Valid Claim</font>&#8221; means a claim (i) 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 (ii) 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 (7) 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 (i) above with respect to such application issues.</div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">88</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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-size: 12pt; font-variant: small-caps; font-weight: bold;"><font style="font-size: 10pt;"><u>Appendix </u></font><font style="font-size: 10pt; color: rgb(0, 0, 0);"><u>2</u></font></div>
        <div><br>
        </div>
        <div style="text-align: center; font-weight: bold;">Isis Development Candidate-R&amp;D Plan</div>
        <div>&#160;</div>
        <div style="text-align: center; font-variant: small-caps;">[***]</div>
        <div><br>
        </div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">89</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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-variant: small-caps; font-weight: bold;"><u>Appendix 3</u></div>
        <div>&#160;</div>
        <div style="text-align: center; font-weight: bold;">Brain Shuttle Development Candidate-R&amp;D Plan</div>
        <div>&#160;</div>
        <div style="text-align: center;">[***]</div>
        <div><br>
        </div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">90</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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-variant: small-caps; font-weight: bold;"><u>Appendix 4</u></div>
        <div>&#160;</div>
        <div style="text-align: center; font-weight: bold;">Isis Development Candidate Checklist</div>
        <div>&#160;</div>
        <div style="text-align: center; font-weight: bold;">[***]</div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">91</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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-variant: small-caps; font-weight: bold;"><u>Appendix 5</u></div>
        <div>&#160;</div>
        <div style="text-align: center; font-weight: bold;">Roche&#8217;s Development and Commercialization Activities and</div>
        <div style="text-align: center; font-weight: bold;">Specific Performance Milestone Events</div>
        <div><br>
        </div>
        <div style="text-align: center;">[***]</div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">92</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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-variant: small-caps; font-weight: bold;"><u>Appendix 6</u></div>
        <div>&#160;</div>
        <div style="text-align: center; font-weight: bold;">Brain Shuttle Collaboration Patents</div>
        <div>&#160;</div>
        <div style="text-align: center; font-weight: bold;">[To be added/updated during Agreement Term]</div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">93</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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-variant: small-caps; font-weight: bold;"><u>Appendix 7</u></div>
        <div>&#160;</div>
        <div style="text-align: center; font-weight: bold;">Relevant Permitted Licenses as of the Effective Date</div>
        <div>&#160;</div>
        <div style="text-align: center; font-size: 12pt; font-weight: bold;"><font style="font-size: 10pt;">[***]</font></div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">94</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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-size: 12pt; font-variant: small-caps; font-weight: bold;"><font style="font-size: 10pt;"><u>Schedule 1.5.1</u></font></div>
        <div><br>
        </div>
        <div style="text-align: center; color: rgb(0, 0, 0); font-variant: small-caps; font-weight: bold;"><u>JSC Governance</u></div>
        <div>&#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="zf7bff87089f9470e95ea9d3ca39fad44">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; color: rgb(0, 0, 0);">One of the primary purposes of the JSC is to empower the JSC to make decisions with respect to the composition and conduct of the R&amp;D Plans that are not
                    specifically vested in a Party under this Agreement. Nothing in this </font><u><font style="font-size: 10pt; font-variant: small-caps; color: rgb(0, 0, 0);">Schedule</font><font style="font-size: 10pt; color: rgb(0, 0, 0);">&#160;</font><font style="font-size: 10pt;">1.5.1</font></u><font style="font-size: 10pt; color: rgb(0, 0, 0);"> is intended to affect any decision-making authority granted to a Party in the body of the Agreement.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zeaeef7bfec5544188eda670fc9f3e36d">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="font-size: 12pt;"><font style="font-size: 10pt; color: rgb(0, 0, 0);">The JSC will begin on the Effective Date and will dissolve upon the first Approval; </font><font style="font-size: 10pt; font-style: italic; color: rgb(0, 0, 0);">provided, however</font><font style="font-size: 10pt; color: rgb(0, 0, 0);">, that Isis&#8217; obligation to participate in the JSC will terminate upon Option exercise. Thereafter, Isis will have the right, but not the obligation, to
                    participate in JSC meetings.</font></div>
              </td>
            </tr>

        </table>
        <div>&#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="zaae7baa0505d4f64bf428dda37861278">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(c)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>The JSC will determine the JSC operating procedures, including frequency of meetings (at least quarterly prior to Option exercise and at least yearly after Option exercise), location of meetings, and responsibilities for agendas and
                  minutes. The JSC will codify these operating procedures in the written minutes of the first meeting.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z614747780b2d462e8ac7e8ef841008e3">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(d)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>The JSC may hold meetings in person or by audio or video conference as determined by the JSC; but at least two meetings per year will be in person (one held at Isis&#8217; facilities, and the other held at Roche&#8217;s facilities). Alliance
                  Managers will attend JSC meetings as participating non-members. In addition, upon prior approval of the other Party, each Party may invite its employees or consultants to attend JSC meetings, including any subject matter expert(s) with
                  valuable knowledge of HTT or Huntington&#8217;s Disease.</div>
              </td>
            </tr>

        </table>
        <div>&#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="z51ec3760d67041a9a356eeae325d491f">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(e)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>The chairperson will be responsible for ensuring that activities occur as set forth in this Agreement, including ensuring that JSC meetings occur, JSC recommendations are properly reflected in the minutes, and any dispute is given
                  prompt attention and resolved in accordance with <u>Section 1.5.2</u>, <u>Section 7.1.3</u> and <u>Section 12.1</u>, as applicable.</div>
              </td>
            </tr>

        </table>
        <div>&#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="zd44819a4860f44c0aac7b8f65fafc3f0">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(f)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>The JSC members from the same Party will collectively have one vote. The JSC will strive to make recommendations with approval of both Isis members and Roche members, and record such recommendations in the minutes of the applicable JSC
                  meeting.</div>
              </td>
            </tr>

        </table>
        <div>&#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="zb4e3496123774bfcb52ad477ac03d44a">

            <tr>
              <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0); font-variant: small-caps; font-weight: bold;">(g)</td>
              <td style="width: auto; vertical-align: top; text-align: center;">
                <div style="text-align: left;">The JSC may form subcommittees and working groups as it determines in order to carry out its activities under this Agreement, all of which will dissolve when the JSC dissolves.</div>
              </td>
            </tr>

        </table>
        <div>&#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="zba9a675b792e4285a3c72eb1d0c28d57">

            <tr>
              <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0); font-weight: bold;">(h)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="color: rgb(0, 0, 0);">Without limiting the provisions of <u>Section 1.5.1</u>, subject to <u>Section 1.5.2</u>, the JSC will perform the following functions:</div>
              </td>
            </tr>

        </table>
        <div>&#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="zc0c27aae97994a2297098c721a27be82">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0);">(i)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="color: rgb(0, 0, 0);">advise on the details and deliverables for the selection of Development Candidates;</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">95</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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" class="DSPFListTable" id="z3a819319547b4c01a2dd8e17a32fc93b" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

              <tr style="vertical-align: top;">
                <td style="width: 36pt;">&#160;</td>
                <td style="vertical-align: top; width: 36pt;">
                  <div style="text-align: justify;"><font style="color: rgb(0, 0, 0);">(ii)</font></div>
                </td>
                <td style="vertical-align: top; width: auto;">
                  <div style="text-align: justify;"><font style="color: rgb(0, 0, 0);">review the overall progress of efforts to select Development Candidates;</font></div>
                </td>
              </tr>

          </table>
        </div>
        <div>&#160;</div>
        <div>
          <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z47014ef095f64532b285b491235faccd" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

              <tr style="vertical-align: top;">
                <td style="width: 36pt;">&#160;</td>
                <td style="vertical-align: top; width: 36pt;">
                  <div style="text-align: justify;"><font style="color: rgb(0, 0, 0);">(iii)</font></div>
                </td>
                <td style="align: left; vertical-align: top; width: auto;">
                  <div style="text-align: justify;"><font style="color: rgb(0, 0, 0);">review emerging data and consider changes to the R&amp;D Plans;</font></div>
                </td>
              </tr>

          </table>
        </div>
        <div>&#160;</div>
        <div>
          <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z06e3acbc11844db3a365f0e515838edd" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

              <tr style="vertical-align: top;">
                <td style="width: 36pt;">&#160;</td>
                <td style="vertical-align: top; width: 36pt;">
                  <div style="text-align: justify;"><font style="color: rgb(0, 0, 0);">(iv)</font></div>
                </td>
                <td style="vertical-align: top; width: auto;">
                  <div style="text-align: justify;"><font style="color: rgb(0, 0, 0);">review, provide advice and recommend revisions to the R&amp;D Plans</font></div>
                </td>
              </tr>

          </table>
        </div>
        <div>&#160;</div>
        <div>
          <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zaeb6da95ab97436eb227f7c1bdd3127b" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

              <tr style="vertical-align: top;">
                <td style="width: 36pt;">&#160;</td>
                <td style="vertical-align: top; width: 36pt;">
                  <div style="text-align: justify;"><font style="color: rgb(0, 0, 0);">(v)</font></div>
                </td>
                <td style="vertical-align: top; width: auto;">
                  <div style="text-align: justify;"><font style="color: rgb(0, 0, 0);">discuss the selection of the Brain Shuttle Development Candidate;</font></div>
                </td>
              </tr>

          </table>
        </div>
        <div>&#160;</div>
        <div>
          <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z4c3ce5075b7347088c50217dee1b5932" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

              <tr style="vertical-align: top;">
                <td style="width: 36pt;">&#160;</td>
                <td style="vertical-align: top; width: 36pt;">
                  <div style="text-align: justify;"><font style="color: rgb(0, 0, 0);">(vi)</font></div>
                </td>
                <td style="vertical-align: top; width: auto;">
                  <div style="text-align: justify;"><font style="color: rgb(0, 0, 0);">materially amend the R&amp;D Plans upon the JSC&#8217;s unanimous written consent;</font></div>
                </td>
              </tr>

          </table>
        </div>
        <div>&#160;</div>
        <div>
          <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z836c2123d24f40e59e4b6aae480ad3fc" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

              <tr style="vertical-align: top;">
                <td style="width: 36pt;">&#160;</td>
                <td style="vertical-align: top; width: 36pt;">
                  <div style="text-align: justify;"><font style="color: rgb(0, 0, 0);">(vii)</font></div>
                </td>
                <td style="vertical-align: top; width: auto;">
                  <div style="text-align: justify;"><font style="color: rgb(0, 0, 0);">record recommendations and decisions of the JSC in the JSC&#8217;s meeting minutes;</font></div>
                </td>
              </tr>

          </table>
        </div>
        <div>&#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="ze2c0bda6ffa148cb85945fa117737061">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0);">(viii)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="color: rgb(0, 0, 0);">such other review and advisory responsibilities assigned to the JSC pursuant to this Agreement; and</div>
              </td>
            </tr>

        </table>
        <div>&#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="z3cf30b9c010c47a7a7af384885f2e129">

            <tr>
              <td style="width: 36pt;"><br>
              </td>
              <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0);">(ix)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div style="color: rgb(0, 0, 0);">discuss whether to continue with Change Overruns.</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">96</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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-size: 12pt; font-variant: small-caps; font-weight: bold;"><u><font style="font-size: 10pt;">Schedule 1.5.3</font></u></div>
        <div>&#160;</div>
        <div style="text-align: center; font-weight: bold;">Alliance Management Activities</div>
        <div>&#160;</div>
        <div>Each Alliance Manager is responsible for:</div>
        <div>&#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="zf9d7a9eef193425e9a7e89c18fdadddb">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(a)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Promoting the overall health of the relationship between the Parties;</div>
              </td>
            </tr>

        </table>
        <div>&#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="z5b60e15c7d2943209057586ddbdd8a9e">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(b)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Developing a mutually agreed alliance launch plan covering any activities and systems that the Parties need to implement within the first one hundred (100) days after the Effective Date to support the R&amp;D Plans;</div>
              </td>
            </tr>

        </table>
        <div>&#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="zecf2d74e8b534023af7601090eb6b8f7">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(c)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Organizing JSC meetings, including agendas, drafting minutes, and publishing final minutes;</div>
              </td>
            </tr>

        </table>
        <div>&#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="zd876794c5e7846e7af24fcae33eb1e16">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(d)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Supporting the co-chairs of the JSC with organization of meetings, information exchange, meeting minutes, and facilitating dispute resolution as necessary;</div>
              </td>
            </tr>

        </table>
        <div>&#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="z359e0e74c8464401a8c0199bdc3213e0">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(e)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Preparing status and progress reports on the above as determined necessary by the JSC;</div>
              </td>
            </tr>

        </table>
        <div>&#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="zb19e2317bfd3410d8088b221f17853b8">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(f)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Ensuring compliance in maintaining the Isis Internal ASO Safety Database as outlined in <u>Section 5.2.2</u>;</div>
              </td>
            </tr>

        </table>
        <div>&#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="z7a67901f17884f3e98f3e411dfc5f951">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(g)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Ensuring proper approval of publications prior to submission as required in <u>Section 11.4</u>; and</div>
              </td>
            </tr>

        </table>
        <div>&#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="ze0b4e45a7b6844b6bb5ca90b062e5425">

            <tr>
              <td style="width: 36pt; vertical-align: top; font-weight: bold;">(h)</td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div>Understanding and communicating the components contained in the relationship-management document provided by Isis to Roche, to assist Roche in understanding and complying with the contractual obligations under the Isis In-License
                  Agreements after Option exercise.</div>
              </td>
            </tr>

        </table>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">97</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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-size: 12pt; font-weight: bold;"><u><font style="font-size: 10pt; font-variant: small-caps;">Schedule</font><font style="font-size: 10pt;">&#160;1.6.2(b)(i)</font></u></div>
        <div><br>
        </div>
        <div style="text-align: center; font-weight: bold;">Cost of ASOs Supplied Under the Brain Shuttle Development Candidate-R&amp;D Plan</div>
        <div>&#160;</div>
        <div style="text-align: center;">[***]</div>
        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">98</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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-variant: small-caps; font-weight: bold;"><u><font style="font-size: 10pt;">Schedule 1.7.1</font></u></div>
        <div><br>
        </div>
        <div style="text-align: center; color: rgb(0, 0, 0); font-weight: bold;">Isis&#8217; Fully Absorbed Cost of Goods Methodology</div>
        <div style="text-align: center; color: rgb(0, 0, 0);">Cost Estimate of API Cost per Kilogram</div>
        <div style="text-align: center; color: rgb(0, 0, 0);">(OOO&#8217;s)</div>
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          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">99</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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-weight: bold;"><u><font style="font-size: 10pt; font-variant: small-caps;">Schedule </font><font style="font-size: 10pt;">6.7.2(e)</font></u></div>
        <div><br>
        </div>
        <div style="text-align: center; font-weight: bold;">Royalty Calculation Examples</div>
        <div>&#160;</div>
        <div style="text-align: center;">[***]</div>
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        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">100</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-weight: bold;"><u><font style="font-size: 10pt; font-variant: small-caps;">Schedule </font><font style="font-size: 10pt;">6.7.2(f)</font></u></div>
        <div>&#160;</div>
        <div style="text-align: center; font-weight: bold;">Allocation of Net Sales</div>
        <div>&#160;</div>
        <div style="text-align: center;">[***]</div>
        <div>&#160;</div>
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          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">101</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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><br>
        </div>
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        <div>&#160;</div>
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        <div><br>
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        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">102</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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>&#160;</div>
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        <div>&#160;</div>
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        <div>&#160;</div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">103</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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><br>
        </div>
        <div style="text-align: center; font-size: 12pt; font-weight: bold;"><u><font style="font-size: 10pt; font-variant: small-caps;">Schedule</font><font style="font-size: 10pt;">&#160;8.2.4(b)</font></u></div>
        <div>&#160;</div>
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        <div>&#160;</div>
        <div style="text-align: center;">[***]</div>
        <div>&#160;</div>
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          <div class="BRPFPageNumberArea" style="text-align: center;"><font class="BRPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal;">104</font></div>
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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-weight: bold;"><u><font style="font-size: 10pt; font-variant: small-caps;">Schedule</font><font style="font-size: 10pt;">&#160;8.2.4(c)</font></u></div>
        <div>&#160;</div>
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        <div>&#160;</div>
        <div style="text-align: center;">[***]</div>
        <div style="text-align: center;"> <br>
        </div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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-variant: small-caps; font-weight: bold;"><u><font style="font-size: 10pt;">Schedule 8.2.7</font></u></div>
        <div><br>
        </div>
        <div style="text-align: center; font-weight: bold;">Prior Agreements</div>
        <div>&#160;</div>
        <div style="text-align: center;">[***]</div>
        <div><br>
        </div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" class="BRPFPageBreakArea">
          <div style="page-break-after: always;" class="BRPFPageBreak">
            <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-variant: small-caps; font-weight: bold;"><u><font style="font-size: 10pt;">Schedule 8.4.1</font></u></div>
        <div><br>
        </div>
        <div style="text-align: center; font-weight: bold;">Roche Existing Brain Shuttle Patents</div>
        <div>&#160;</div>
        <div style="text-align: center; color: rgb(0, 0, 0);">[***]</div>
        <div><br>
        </div>
        <div>&#160;</div>
      </div>
      <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-31.1
<SEQUENCE>6
<FILENAME>ex31-1.htm
<DESCRIPTION>EXHIBIT 31.1
<TEXT>
<html><head>
    <title>&nbsp;</title>
    <!-- Licensed to: Ionis Pharmaceuticals
         Document created using Broadridge PROfile 23.3.1.5138
         Copyright 1995 - 2023 Broadridge -->
  </head><body style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div id="TRGRSegment:956881ca-11d1-4726-85b7-68a37548513a"><div style="text-align: right; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><font style="font-family: Calibri; font-size: 12pt;"><hr style="height: 4px; color: #000000; background-color: #000000; text-align: center; margin-left: auto; margin-right: auto; border: none" noshade="noshade" align="center"></font>EXHIBIT 31.1</div><div><br></div><div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">CERTIFICATION</div><div><br></div><div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">I, Brett P. Monia, certify that:</div><div><br></div><table style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="z2d48b6942c1c4131b7dd6f4d3c543308"><tr><td style="width: 18pt;"></td><td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">1.</td><td style="width: auto; vertical-align: top; text-align: justify;"><div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">I have reviewed this Quarterly Report on Form 10-Q of Ionis Pharmaceuticals, Inc.;</div></td></tr></table><div><br></div><table style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="z3f157ea43bed449388171b512434c390"><tr><td style="width: 18pt;"></td><td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">2.</td><td style="width: auto; vertical-align: top; text-align: justify;"><div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Based on my knowledge, this quarterly 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 quarterly report;</div></td></tr></table><div><br></div><table style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="zd854b968782f4204b4da095a7b0ad6f1"><tr><td style="width: 18pt;"></td><td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">3.</td><td style="width: auto; vertical-align: top; text-align: justify;"><div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Based on my knowledge, the condensed consolidated financial statements, and other financial information included in this quarterly report, fairly present in all material respects the financial condition, condensed consolidated results of operations and condensed consolidated cash flows of the registrant as of, and for, the periods presented in this quarterly report;</div></td></tr></table><div><br></div><table style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="z6f19bb8c40824c74be7bf1d95c579e5f"><tr><td style="width: 18pt;"></td><td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">4.</td><td style="width: auto; vertical-align: top; text-align: justify;"><div style="color: #000000; font-family: 'Times New Roman'; 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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="z30bac194c62d405fab37aba6e7ab4c78"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">a)</td><td style="width: auto; vertical-align: top; text-align: justify;"><div style="color: #000000; font-family: 'Times New Roman'; 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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="z5c001c6fac954b2b8b12fa5d9c7e5f9c"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">b)</td><td style="width: auto; vertical-align: top; text-align: justify;"><div style="color: #000000; font-family: 'Times New Roman'; 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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="ze383b0ab1db6483faf4d469eacc35278"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">c)</td><td style="width: auto; vertical-align: top; text-align: justify;"><div style="color: #000000; font-family: 'Times New Roman'; 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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="z9dc6edf082f04108a4d36ceeb7801b44"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">d)</td><td style="width: auto; vertical-align: top; text-align: justify;"><div style="color: #000000; font-family: 'Times New Roman'; 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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="z6dc924e3568f4160a01eb878151aa9ae"><tr><td style="width: 18pt;"></td><td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">5.</td><td style="width: auto; vertical-align: top; text-align: justify;"><div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">The registrant&#8217;s other certifying officer and I have disclosed, based on our most recent evaluation of internal control over financial reporting, to the registrant&#8217;s auditors and the audit committee of registrant&#8217;s board of directors (or persons performing the equivalent functions):</div></td></tr></table><div><br></div><table style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="z04d1cda8b8e84633b4239c12e36d2180"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">a)</td><td style="width: auto; vertical-align: top; text-align: justify;"><div style="color: #000000; font-family: 'Times New Roman'; 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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="z75288ae016774d3dbcba417bbfdacf32"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">b)</td><td style="width: auto; vertical-align: top; text-align: justify;"><div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">&#160;</div><div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#160;</div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="z07d4ca9b4b784189b85fa4b9c332f16f"><tr><td style="width: 27.59%; vertical-align: top;"><div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Dated: May 3, 2023</div></td><td style="width: 72.41%; vertical-align: top;"><div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#160;</div></td></tr><tr><td style="width: 27.59%; vertical-align: top;"><div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#160;</div></td><td style="width: 72.41%; vertical-align: top;"><div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#160;</div></td></tr><tr><td style="width: 27.59%; vertical-align: top; border-bottom: #000000 2px solid;"><div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">/s/ BRETT P. MONIA</div></td><td style="width: 72.41%; vertical-align: top;"><div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#160;</div></td></tr><tr><td style="width: 27.59%; vertical-align: top;"><div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Brett P. Monia, Ph.D.</div></td><td style="width: 72.41%; vertical-align: top;"><div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#160;</div></td></tr><tr><td style="width: 27.59%; vertical-align: top;"><div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Chief Executive Officer</div></td><td style="width: 72.41%; vertical-align: top;"><div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#160;</div></td></tr></table><div><br></div><div style="text-align: justify; font-family: Calibri; font-size: 12pt;"><hr style="height: 2px; color: #000000; background-color: #000000; text-align: center; margin-left: auto; margin-right: auto; border: none" noshade="noshade" align="center"></div></div></body></html>
</TEXT>
</DOCUMENT>
<DOCUMENT>
<TYPE>EX-31.2
<SEQUENCE>7
<FILENAME>ex31-2.htm
<DESCRIPTION>EXHIBIT 31.2
<TEXT>
<html><head>
    <title>&nbsp;</title>
    <!-- Licensed to: Ionis Pharmaceuticals
         Document created using Broadridge PROfile 23.3.1.5138
         Copyright 1995 - 2023 Broadridge -->
  </head><body style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div id="TRGRSegment:9770b480-fdae-48ad-8dab-7c414e81bcac"><div style="text-align: right; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><font style="font-family: Calibri; font-size: 12pt;"><hr style="height: 4px; color: #000000; background-color: #000000; text-align: center; margin-left: auto; margin-right: auto; border: none" noshade="noshade" align="center"></font>EXHIBIT 31.2</div><div><br></div><div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">CERTIFICATION</div><div><br></div><div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">I, Elizabeth L. Hougen, certify that:</div><div><br></div><table style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="z6486485fd53e47508bb64f3f02fb5fa4"><tr><td style="width: 18pt;"></td><td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">1.</td><td style="width: auto; vertical-align: top; text-align: justify;"><div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">I have reviewed this Quarterly Report on Form 10-Q of Ionis Pharmaceuticals, Inc.;</div></td></tr></table><div><br></div><table style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" cellpadding="0" cellspacing="0" id="z4e6957ad7e3646499a1997fd8e17b790"><tr><td style="width: 18pt;"></td><td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; 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<TYPE>EX-101.CAL
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<DOCUMENT>
<TYPE>EX-101.LAB
<SEQUENCE>12
<FILENAME>ions-20230331_lab.xml
<DESCRIPTION>XBRL TAXONOMY EXTENSION LABEL LINKBASE
<TEXT>
<XBRL>
<?xml version="1.0" encoding="us-ascii"?>
<!--Generated by Broadridge PROfile 23.3.2.5148 Broadridge-->
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AccruedLiabilitiesCurrent" xlink:label="AccruedLiabilitiesCurrent" xlink:title="AccruedLiabilitiesCurrent" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AllocatedShareBasedCompensationExpense" xlink:label="AllocatedShareBasedCompensationExpense" xlink:title="AllocatedShareBasedCompensationExpense" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_AllocatedShareBasedCompensationExpense_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AllocatedShareBasedCompensationExpense_lbl1" xml:lang="en-US" id="us-gaap_AllocatedShareBasedCompensationExpense_lbl1">Share-Based Payment Arrangement, Expense</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_AmortizationOfFinancingCosts_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AmortizationOfFinancingCosts_lbl1" xml:lang="en-US" id="us-gaap_AmortizationOfFinancingCosts_lbl1">Amortization of Debt Issuance Costs</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AssetsFairValueDisclosure" xlink:label="AssetsFairValueDisclosure" xlink:title="AssetsFairValueDisclosure" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AssetsFairValueDisclosure_lbl" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_AssetsFairValueDisclosure_lbl" xml:lang="en-US" id="us-gaap_AssetsFairValueDisclosure_lbl">Total</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AssetsAbstract" xlink:label="AssetsAbstract" xlink:title="AssetsAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AssetsAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_AssetsAbstract_lbl" xml:lang="en-US" id="us-gaap_AssetsAbstract_lbl">ASSETS</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_AssetsAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AssetsAbstract_lbl1" xml:lang="en-US" id="us-gaap_AssetsAbstract_lbl1">Assets [Abstract]</link:label>
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Assets" xlink:to="us-gaap_Assets_lbl" xlink:title="label: Assets to us-gaap_Assets_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_Assets_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_Assets_lbl1" xml:lang="en-US" id="us-gaap_Assets_lbl1">Assets</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Assets" xlink:to="us-gaap_Assets_lbl1" xlink:title="label: Assets to us-gaap_Assets_lbl1" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_AssetsCurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_AssetsCurrent_lbl" xml:lang="en-US" id="us-gaap_AssetsCurrent_lbl">Total current assets</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AssetsCurrent" xlink:to="us-gaap_AssetsCurrent_lbl" xlink:title="label: AssetsCurrent to us-gaap_AssetsCurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AssetsCurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AssetsCurrent_lbl1" xml:lang="en-US" id="us-gaap_AssetsCurrent_lbl1">Assets, Current</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AssetsCurrent" xlink:to="us-gaap_AssetsCurrent_lbl1" xlink:title="label: AssetsCurrent to us-gaap_AssetsCurrent_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_AssetsCurrentAbstract" xlink:label="AssetsCurrentAbstract" xlink:title="AssetsCurrentAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AssetsCurrentAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_AssetsCurrentAbstract_lbl" xml:lang="en-US" id="us-gaap_AssetsCurrentAbstract_lbl">Current assets:</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_CashFlowNoncashInvestingAndFinancingActivitiesDisclosureAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_CashFlowNoncashInvestingAndFinancingActivitiesDisclosureAbstract_lbl1" xml:lang="en-US" id="us-gaap_CashFlowNoncashInvestingAndFinancingActivitiesDisclosureAbstract_lbl1">Cash Flow, Noncash Investing and Financing Activities Disclosure [Abstract]</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_CollaborativeArrangementDisclosureTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_CollaborativeArrangementDisclosureTextBlock_lbl" xml:lang="en-US" id="us-gaap_CollaborativeArrangementDisclosureTextBlock_lbl">Collaborative Arrangements and Licensing Agreements</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_CommitmentsAndContingenciesDisclosureAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_CommitmentsAndContingenciesDisclosureAbstract_lbl" xml:lang="en-US" id="us-gaap_CommitmentsAndContingenciesDisclosureAbstract_lbl">Legal Proceedings [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CommitmentsAndContingenciesDisclosureAbstract" xlink:to="us-gaap_CommitmentsAndContingenciesDisclosureAbstract_lbl" xlink:title="label: CommitmentsAndContingenciesDisclosureAbstract to us-gaap_CommitmentsAndContingenciesDisclosureAbstract_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CommonStockMember" xlink:label="CommonStockMember" xlink:title="CommonStockMember" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_ConcentrationRiskTypeDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ConcentrationRiskTypeDomain_lbl" xml:lang="en-US" id="us-gaap_ConcentrationRiskTypeDomain_lbl">Concentration Risk Type [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConcentrationRiskTypeDomain" xlink:to="us-gaap_ConcentrationRiskTypeDomain_lbl" xlink:title="label: ConcentrationRiskTypeDomain to us-gaap_ConcentrationRiskTypeDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ConcentrationRiskBenchmarkDomain" xlink:label="ConcentrationRiskBenchmarkDomain" xlink:title="ConcentrationRiskBenchmarkDomain" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ConcentrationRiskBenchmarkDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ConcentrationRiskBenchmarkDomain_lbl" xml:lang="en-US" id="us-gaap_ConcentrationRiskBenchmarkDomain_lbl">Concentration Risk Benchmark [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConcentrationRiskBenchmarkDomain" xlink:to="us-gaap_ConcentrationRiskBenchmarkDomain_lbl" xlink:title="label: ConcentrationRiskBenchmarkDomain to us-gaap_ConcentrationRiskBenchmarkDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ConcentrationRiskPercentage1" xlink:label="ConcentrationRiskPercentage1" xlink:title="ConcentrationRiskPercentage1" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ConcentrationRiskPercentage1_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ConcentrationRiskPercentage1_lbl" xml:lang="en-US" id="us-gaap_ConcentrationRiskPercentage1_lbl">Concentration percentage</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConcentrationRiskPercentage1" xlink:to="us-gaap_ConcentrationRiskPercentage1_lbl" xlink:title="label: ConcentrationRiskPercentage1 to us-gaap_ConcentrationRiskPercentage1_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ConcentrationRiskByBenchmarkAxis" xlink:label="ConcentrationRiskByBenchmarkAxis" xlink:title="ConcentrationRiskByBenchmarkAxis" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ConcentrationRiskByBenchmarkAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ConcentrationRiskByBenchmarkAxis_lbl" xml:lang="en-US" id="us-gaap_ConcentrationRiskByBenchmarkAxis_lbl">Concentration Risk Benchmark [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConcentrationRiskByBenchmarkAxis" xlink:to="us-gaap_ConcentrationRiskByBenchmarkAxis_lbl" xlink:title="label: ConcentrationRiskByBenchmarkAxis to us-gaap_ConcentrationRiskByBenchmarkAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ConsolidationPolicyTextBlock" xlink:label="ConsolidationPolicyTextBlock" xlink:title="ConsolidationPolicyTextBlock" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ConsolidationPolicyTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ConsolidationPolicyTextBlock_lbl" xml:lang="en-US" id="us-gaap_ConsolidationPolicyTextBlock_lbl">Consolidation</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConsolidationPolicyTextBlock" xlink:to="us-gaap_ConsolidationPolicyTextBlock_lbl" xlink:title="label: ConsolidationPolicyTextBlock to us-gaap_ConsolidationPolicyTextBlock_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ContractWithCustomerLiabilityCurrent" xlink:label="ContractWithCustomerLiabilityCurrent" xlink:title="ContractWithCustomerLiabilityCurrent" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ContractWithCustomerLiabilityCurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="us-gaap_ContractWithCustomerLiabilityCurrent_lbl" xml:lang="en-US" id="us-gaap_ContractWithCustomerLiabilityCurrent_lbl">Current portion of deferred contract revenue</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ContractWithCustomerLiabilityCurrent" xlink:to="us-gaap_ContractWithCustomerLiabilityCurrent_lbl" xlink:title="label: ContractWithCustomerLiabilityCurrent to us-gaap_ContractWithCustomerLiabilityCurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ContractWithCustomerLiabilityCurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ContractWithCustomerLiabilityCurrent_lbl1" xml:lang="en-US" id="us-gaap_ContractWithCustomerLiabilityCurrent_lbl1">Contract with Customer, Liability, Current</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ContractWithCustomerLiabilityCurrent" xlink:to="us-gaap_ContractWithCustomerLiabilityCurrent_lbl1" xlink:title="label: ContractWithCustomerLiabilityCurrent to us-gaap_ContractWithCustomerLiabilityCurrent_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ContractWithCustomerLiability" xlink:label="ContractWithCustomerLiability" xlink:title="ContractWithCustomerLiability" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ContractWithCustomerLiability_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_ContractWithCustomerLiability_lbl" xml:lang="en-US" id="us-gaap_ContractWithCustomerLiability_lbl">Deferred revenue</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ContractWithCustomerLiability" xlink:to="us-gaap_ContractWithCustomerLiability_lbl" xlink:title="label: ContractWithCustomerLiability to us-gaap_ContractWithCustomerLiability_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ContractWithCustomerLiability_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ContractWithCustomerLiability_lbl1" xml:lang="en-US" id="us-gaap_ContractWithCustomerLiability_lbl1">Contract with Customer, Liability</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ContractWithCustomerLiability" xlink:to="us-gaap_ContractWithCustomerLiability_lbl1" xlink:title="label: ContractWithCustomerLiability to us-gaap_ContractWithCustomerLiability_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ContractWithCustomerAssetNetCurrent" xlink:label="ContractWithCustomerAssetNetCurrent" xlink:title="ContractWithCustomerAssetNetCurrent" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ContractWithCustomerAssetNetCurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_ContractWithCustomerAssetNetCurrent_lbl" xml:lang="en-US" id="us-gaap_ContractWithCustomerAssetNetCurrent_lbl">Contracts receivable</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ContractWithCustomerAssetNetCurrent" xlink:to="us-gaap_ContractWithCustomerAssetNetCurrent_lbl" xlink:title="label: ContractWithCustomerAssetNetCurrent to us-gaap_ContractWithCustomerAssetNetCurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ContractWithCustomerAssetNetCurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ContractWithCustomerAssetNetCurrent_lbl1" xml:lang="en-US" id="us-gaap_ContractWithCustomerAssetNetCurrent_lbl1">Contract with Customer, Asset, after Allowance for Credit Loss, Current</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ContractWithCustomerAssetNetCurrent" xlink:to="us-gaap_ContractWithCustomerAssetNetCurrent_lbl1" xlink:title="label: ContractWithCustomerAssetNetCurrent to us-gaap_ContractWithCustomerAssetNetCurrent_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ContractWithCustomerLiabilityNoncurrent" xlink:label="ContractWithCustomerLiabilityNoncurrent" xlink:title="ContractWithCustomerLiabilityNoncurrent" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ContractWithCustomerLiabilityNoncurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="us-gaap_ContractWithCustomerLiabilityNoncurrent_lbl" xml:lang="en-US" id="us-gaap_ContractWithCustomerLiabilityNoncurrent_lbl">Long-term deferred contract revenue</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ContractWithCustomerLiabilityNoncurrent" xlink:to="us-gaap_ContractWithCustomerLiabilityNoncurrent_lbl" xlink:title="label: ContractWithCustomerLiabilityNoncurrent to us-gaap_ContractWithCustomerLiabilityNoncurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ContractWithCustomerLiabilityNoncurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ContractWithCustomerLiabilityNoncurrent_lbl1" xml:lang="en-US" id="us-gaap_ContractWithCustomerLiabilityNoncurrent_lbl1">Contract with Customer, Liability, Noncurrent</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ContractWithCustomerLiabilityNoncurrent" xlink:to="us-gaap_ContractWithCustomerLiabilityNoncurrent_lbl1" xlink:title="label: ContractWithCustomerLiabilityNoncurrent to us-gaap_ContractWithCustomerLiabilityNoncurrent_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.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 Debt, Noncurrent</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/2022/elts/us-gaap-2022.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/2022/elts/us-gaap-2022.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/2022/elts/us-gaap-2022.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" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CostOfGoodsAndServicesSold" xlink:label="CostOfGoodsAndServicesSold" xlink:title="CostOfGoodsAndServicesSold" />
    <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>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CostOfGoodsAndServicesSold" xlink:to="us-gaap_CostOfGoodsAndServicesSold_lbl" xlink:title="label: CostOfGoodsAndServicesSold to us-gaap_CostOfGoodsAndServicesSold_lbl" />
    <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/2022/elts/us-gaap-2022.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>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CostOfSalesMember" xlink:to="us-gaap_CostOfSalesMember_lbl" xlink:title="label: CostOfSalesMember to us-gaap_CostOfSalesMember_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_CostOfSalesMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_CostOfSalesMember_lbl1" xml:lang="en-US" id="us-gaap_CostOfSalesMember_lbl1">Cost of Sales [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CostOfSalesMember" xlink:to="us-gaap_CostOfSalesMember_lbl1" xlink:title="label: CostOfSalesMember to us-gaap_CostOfSalesMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CostsAndExpensesAbstract" xlink:label="CostsAndExpensesAbstract" xlink:title="CostsAndExpensesAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_CostsAndExpensesAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_CostsAndExpensesAbstract_lbl" xml:lang="en-US" id="us-gaap_CostsAndExpensesAbstract_lbl">Expenses:</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CostsAndExpensesAbstract" xlink:to="us-gaap_CostsAndExpensesAbstract_lbl" xlink:title="label: CostsAndExpensesAbstract to us-gaap_CostsAndExpensesAbstract_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_CostsAndExpensesAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_CostsAndExpensesAbstract_lbl1" xml:lang="en-US" id="us-gaap_CostsAndExpensesAbstract_lbl1">Costs and Expenses [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CostsAndExpensesAbstract" xlink:to="us-gaap_CostsAndExpensesAbstract_lbl1" xlink:title="label: CostsAndExpensesAbstract to us-gaap_CostsAndExpensesAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_CostsAndExpenses" xlink:label="CostsAndExpenses" xlink:title="CostsAndExpenses" />
    <link:label xlink:type="resource" xlink:label="us-gaap_CostsAndExpenses_lbl" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_CostsAndExpenses_lbl" xml:lang="en-US" id="us-gaap_CostsAndExpenses_lbl">Total operating expenses</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CostsAndExpenses" xlink:to="us-gaap_CostsAndExpenses_lbl" xlink:title="label: CostsAndExpenses to us-gaap_CostsAndExpenses_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_CostsAndExpenses_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_CostsAndExpenses_lbl1" xml:lang="en-US" id="us-gaap_CostsAndExpenses_lbl1">Costs and Expenses</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CostsAndExpenses" xlink:to="us-gaap_CostsAndExpenses_lbl1" xlink:title="label: CostsAndExpenses to us-gaap_CostsAndExpenses_lbl1" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DebtSecuritiesAvailableForSaleUnrealizedLossPosition" xlink:label="DebtSecuritiesAvailableForSaleUnrealizedLossPosition" xlink:title="DebtSecuritiesAvailableForSaleUnrealizedLossPosition" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DebtDisclosureAbstract" xlink:label="DebtDisclosureAbstract" xlink:title="DebtDisclosureAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtDisclosureAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DebtDisclosureAbstract_lbl" xml:lang="en-US" id="us-gaap_DebtDisclosureAbstract_lbl">Convertible Debt [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtDisclosureAbstract" xlink:to="us-gaap_DebtDisclosureAbstract_lbl" xlink:title="label: DebtDisclosureAbstract to us-gaap_DebtDisclosureAbstract_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DebtInstrumentRepurchasedFaceAmount" xlink:label="DebtInstrumentRepurchasedFaceAmount" xlink:title="DebtInstrumentRepurchasedFaceAmount" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentRepurchasedFaceAmount_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DebtInstrumentRepurchasedFaceAmount_lbl" xml:lang="en-US" id="us-gaap_DebtInstrumentRepurchasedFaceAmount_lbl">Principal amount repurchased</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentRepurchasedFaceAmount" xlink:to="us-gaap_DebtInstrumentRepurchasedFaceAmount_lbl" xlink:title="label: DebtInstrumentRepurchasedFaceAmount to us-gaap_DebtInstrumentRepurchasedFaceAmount_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DebtInstrumentConvertibleConversionPrice1" xlink:label="DebtInstrumentConvertibleConversionPrice1" xlink:title="DebtInstrumentConvertibleConversionPrice1" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentConvertibleConversionPrice1_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DebtInstrumentConvertibleConversionPrice1_lbl" xml:lang="en-US" id="us-gaap_DebtInstrumentConvertibleConversionPrice1_lbl">Conversion 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="DebtInstrumentConvertibleConversionPrice1" xlink:to="us-gaap_DebtInstrumentConvertibleConversionPrice1_lbl" xlink:title="label: DebtInstrumentConvertibleConversionPrice1 to us-gaap_DebtInstrumentConvertibleConversionPrice1_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DebtInstrumentTable" xlink:label="DebtInstrumentTable" xlink:title="DebtInstrumentTable" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentTable_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DebtInstrumentTable_lbl" xml:lang="en-US" id="us-gaap_DebtInstrumentTable_lbl">Schedule of Long-term Debt Instruments [Table]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentTable" xlink:to="us-gaap_DebtInstrumentTable_lbl" xlink:title="label: DebtInstrumentTable to us-gaap_DebtInstrumentTable_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DebtDisclosureTextBlock" xlink:label="DebtDisclosureTextBlock" xlink:title="DebtDisclosureTextBlock" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtDisclosureTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_DebtDisclosureTextBlock_lbl" xml:lang="en-US" id="us-gaap_DebtDisclosureTextBlock_lbl">Convertible Debt</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtDisclosureTextBlock" xlink:to="us-gaap_DebtDisclosureTextBlock_lbl" xlink:title="label: DebtDisclosureTextBlock to us-gaap_DebtDisclosureTextBlock_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtDisclosureTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DebtDisclosureTextBlock_lbl1" xml:lang="en-US" id="us-gaap_DebtDisclosureTextBlock_lbl1">Debt Disclosure [Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtDisclosureTextBlock" xlink:to="us-gaap_DebtDisclosureTextBlock_lbl1" xlink:title="label: DebtDisclosureTextBlock to us-gaap_DebtDisclosureTextBlock_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DebtInstrumentCarryingAmount" xlink:label="DebtInstrumentCarryingAmount" xlink:title="DebtInstrumentCarryingAmount" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentCarryingAmount_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DebtInstrumentCarryingAmount_lbl" xml:lang="en-US" id="us-gaap_DebtInstrumentCarryingAmount_lbl">Outstanding principal balance</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentCarryingAmount" xlink:to="us-gaap_DebtInstrumentCarryingAmount_lbl" xlink:title="label: DebtInstrumentCarryingAmount to us-gaap_DebtInstrumentCarryingAmount_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DebtInstrumentAxis" xlink:label="DebtInstrumentAxis" xlink:title="DebtInstrumentAxis" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DebtInstrumentAxis_lbl" xml:lang="en-US" id="us-gaap_DebtInstrumentAxis_lbl">Debt Instrument [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentAxis" xlink:to="us-gaap_DebtInstrumentAxis_lbl" xlink:title="label: DebtInstrumentAxis to us-gaap_DebtInstrumentAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DebtInstrumentLineItems" xlink:label="DebtInstrumentLineItems" xlink:title="DebtInstrumentLineItems" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentLineItems_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DebtInstrumentLineItems_lbl" xml:lang="en-US" id="us-gaap_DebtInstrumentLineItems_lbl">Debt Instrument [Line Items]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentLineItems" xlink:to="us-gaap_DebtInstrumentLineItems_lbl" xlink:title="label: DebtInstrumentLineItems to us-gaap_DebtInstrumentLineItems_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DebtInstrumentFaceAmount" xlink:label="DebtInstrumentFaceAmount" xlink:title="DebtInstrumentFaceAmount" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentFaceAmount_lbl" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="us-gaap_DebtInstrumentFaceAmount_lbl" xml:lang="en-US" id="us-gaap_DebtInstrumentFaceAmount_lbl">Face amount of offering</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentFaceAmount" xlink:to="us-gaap_DebtInstrumentFaceAmount_lbl" xlink:title="label: DebtInstrumentFaceAmount to us-gaap_DebtInstrumentFaceAmount_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentFaceAmount_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DebtInstrumentFaceAmount_lbl1" xml:lang="en-US" id="us-gaap_DebtInstrumentFaceAmount_lbl1">Debt Instrument, Face Amount</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentFaceAmount" xlink:to="us-gaap_DebtInstrumentFaceAmount_lbl1" xlink:title="label: DebtInstrumentFaceAmount to us-gaap_DebtInstrumentFaceAmount_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DebtInstrumentInterestRateEffectivePercentage" xlink:label="DebtInstrumentInterestRateEffectivePercentage" xlink:title="DebtInstrumentInterestRateEffectivePercentage" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentInterestRateEffectivePercentage_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_DebtInstrumentInterestRateEffectivePercentage_lbl" xml:lang="en-US" id="us-gaap_DebtInstrumentInterestRateEffectivePercentage_lbl">Effective interest rate</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentInterestRateEffectivePercentage" xlink:to="us-gaap_DebtInstrumentInterestRateEffectivePercentage_lbl" xlink:title="label: DebtInstrumentInterestRateEffectivePercentage to us-gaap_DebtInstrumentInterestRateEffectivePercentage_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentInterestRateEffectivePercentage_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DebtInstrumentInterestRateEffectivePercentage_lbl1" xml:lang="en-US" id="us-gaap_DebtInstrumentInterestRateEffectivePercentage_lbl1">Debt Instrument, Interest Rate, Effective Percentage</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentInterestRateEffectivePercentage" xlink:to="us-gaap_DebtInstrumentInterestRateEffectivePercentage_lbl1" xlink:title="label: DebtInstrumentInterestRateEffectivePercentage to us-gaap_DebtInstrumentInterestRateEffectivePercentage_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DebtInstrumentInterestRateStatedPercentage" xlink:label="DebtInstrumentInterestRateStatedPercentage" xlink:title="DebtInstrumentInterestRateStatedPercentage" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentInterestRateStatedPercentage_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_DebtInstrumentInterestRateStatedPercentage_lbl" xml:lang="en-US" id="us-gaap_DebtInstrumentInterestRateStatedPercentage_lbl">Interest rate on convertible senior notes</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentInterestRateStatedPercentage" xlink:to="us-gaap_DebtInstrumentInterestRateStatedPercentage_lbl" xlink:title="label: DebtInstrumentInterestRateStatedPercentage to us-gaap_DebtInstrumentInterestRateStatedPercentage_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentInterestRateStatedPercentage_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DebtInstrumentInterestRateStatedPercentage_lbl1" xml:lang="en-US" id="us-gaap_DebtInstrumentInterestRateStatedPercentage_lbl1">Interest rate</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentInterestRateStatedPercentage" xlink:to="us-gaap_DebtInstrumentInterestRateStatedPercentage_lbl1" xlink:title="label: DebtInstrumentInterestRateStatedPercentage to us-gaap_DebtInstrumentInterestRateStatedPercentage_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DebtInstrumentNameDomain" xlink:label="DebtInstrumentNameDomain" xlink:title="DebtInstrumentNameDomain" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentNameDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DebtInstrumentNameDomain_lbl" xml:lang="en-US" id="us-gaap_DebtInstrumentNameDomain_lbl">Debt Instrument, Name [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentNameDomain" xlink:to="us-gaap_DebtInstrumentNameDomain_lbl" xlink:title="label: DebtInstrumentNameDomain to us-gaap_DebtInstrumentNameDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DebtInstrumentMaturityDate" xlink:label="DebtInstrumentMaturityDate" xlink:title="DebtInstrumentMaturityDate" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentMaturityDate_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DebtInstrumentMaturityDate_lbl" xml:lang="en-US" id="us-gaap_DebtInstrumentMaturityDate_lbl">Maturity date</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentMaturityDate" xlink:to="us-gaap_DebtInstrumentMaturityDate_lbl" xlink:title="label: DebtInstrumentMaturityDate to us-gaap_DebtInstrumentMaturityDate_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DebtSecuritiesMember" xlink:label="DebtSecuritiesMember" xlink:title="DebtSecuritiesMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtSecuritiesMember_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_DebtSecuritiesMember_lbl" xml:lang="en-US" id="us-gaap_DebtSecuritiesMember_lbl">Available-for-sale Debt Securities [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtSecuritiesMember" xlink:to="us-gaap_DebtSecuritiesMember_lbl" xlink:title="label: DebtSecuritiesMember to us-gaap_DebtSecuritiesMember_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtSecuritiesMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DebtSecuritiesMember_lbl1" xml:lang="en-US" id="us-gaap_DebtSecuritiesMember_lbl1">Debt Securities [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtSecuritiesMember" xlink:to="us-gaap_DebtSecuritiesMember_lbl1" xlink:title="label: DebtSecuritiesMember to us-gaap_DebtSecuritiesMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DeferredFinanceCostsNet" xlink:label="DeferredFinanceCostsNet" xlink:title="DeferredFinanceCostsNet" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DeferredFinanceCostsNet_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_DeferredFinanceCostsNet_lbl" xml:lang="en-US" id="us-gaap_DeferredFinanceCostsNet_lbl">Unamortized debt issuance costs</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DeferredFinanceCostsNet" xlink:to="us-gaap_DeferredFinanceCostsNet_lbl" xlink:title="label: DeferredFinanceCostsNet to us-gaap_DeferredFinanceCostsNet_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DeferredFinanceCostsNet_lbl1" xlink:role="http://www.xbrl.org/2009/role/negatedTerseLabel" xlink:title="us-gaap_DeferredFinanceCostsNet_lbl1" xml:lang="en-US" id="us-gaap_DeferredFinanceCostsNet_lbl1">Net issuance costs related to sale of future royalties</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DeferredFinanceCostsNet" xlink:to="us-gaap_DeferredFinanceCostsNet_lbl1" xlink:title="label: DeferredFinanceCostsNet to us-gaap_DeferredFinanceCostsNet_lbl1" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DeferredFinanceCostsNet_lbl2" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DeferredFinanceCostsNet_lbl2" xml:lang="en-US" id="us-gaap_DeferredFinanceCostsNet_lbl2">Debt Issuance Costs, Net</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DeferredFinanceCostsNet" xlink:to="us-gaap_DeferredFinanceCostsNet_lbl2" xlink:title="label: DeferredFinanceCostsNet to us-gaap_DeferredFinanceCostsNet_lbl2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_Depreciation" xlink:label="Depreciation" xlink:title="Depreciation" />
    <link:label xlink:type="resource" xlink:label="us-gaap_Depreciation_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_Depreciation_lbl" xml:lang="en-US" id="us-gaap_Depreciation_lbl">Depreciation</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Depreciation" xlink:to="us-gaap_Depreciation_lbl" xlink:title="label: Depreciation to us-gaap_Depreciation_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_Depreciation_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_Depreciation_lbl1" xml:lang="en-US" id="us-gaap_Depreciation_lbl1">Depreciation</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Depreciation" xlink:to="us-gaap_Depreciation_lbl1" xlink:title="label: Depreciation to us-gaap_Depreciation_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_DisclosureOfCompensationRelatedCostsShareBasedPaymentsTextBlock" xlink:label="DisclosureOfCompensationRelatedCostsShareBasedPaymentsTextBlock" xlink:title="DisclosureOfCompensationRelatedCostsShareBasedPaymentsTextBlock" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DisclosureOfCompensationRelatedCostsShareBasedPaymentsTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_DisclosureOfCompensationRelatedCostsShareBasedPaymentsTextBlock_lbl" xml:lang="en-US" id="us-gaap_DisclosureOfCompensationRelatedCostsShareBasedPaymentsTextBlock_lbl">Stock-based Compensation Expense</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DisclosureOfCompensationRelatedCostsShareBasedPaymentsTextBlock" xlink:to="us-gaap_DisclosureOfCompensationRelatedCostsShareBasedPaymentsTextBlock_lbl" xlink:title="label: DisclosureOfCompensationRelatedCostsShareBasedPaymentsTextBlock to us-gaap_DisclosureOfCompensationRelatedCostsShareBasedPaymentsTextBlock_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DisclosureOfCompensationRelatedCostsShareBasedPaymentsTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DisclosureOfCompensationRelatedCostsShareBasedPaymentsTextBlock_lbl1" xml:lang="en-US" id="us-gaap_DisclosureOfCompensationRelatedCostsShareBasedPaymentsTextBlock_lbl1">Share-Based Payment Arrangement [Text Block]</link:label>
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EmployeeRelatedLiabilitiesCurrent" xlink:to="us-gaap_EmployeeRelatedLiabilitiesCurrent_lbl1" xlink:title="label: EmployeeRelatedLiabilitiesCurrent to us-gaap_EmployeeRelatedLiabilitiesCurrent_lbl1" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquitySecuritiesFvNiUnrealizedGain" xlink:to="us-gaap_EquitySecuritiesFvNiUnrealizedGain_lbl1" xlink:title="label: EquitySecuritiesFvNiUnrealizedGain to us-gaap_EquitySecuritiesFvNiUnrealizedGain_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EquitySecuritiesFvNiUnrealizedLoss" xlink:label="EquitySecuritiesFvNiUnrealizedLoss" xlink:title="EquitySecuritiesFvNiUnrealizedLoss" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_EquitySecuritiesFvNiUnrealizedLoss_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_EquitySecuritiesFvNiUnrealizedLoss_lbl1" xml:lang="en-US" id="us-gaap_EquitySecuritiesFvNiUnrealizedLoss_lbl1">Equity Securities, FV-NI, Unrealized Loss</link:label>
    <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/2022/elts/us-gaap-2022.xsd#us-gaap_EquitySecuritiesFVNIAbstract" xlink:label="EquitySecuritiesFVNIAbstract" xlink:title="EquitySecuritiesFVNIAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_EquitySecuritiesFVNIAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_EquitySecuritiesFVNIAbstract_lbl" xml:lang="en-US" id="us-gaap_EquitySecuritiesFVNIAbstract_lbl">Equity Securities [Abstract]</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_EquityComponentDomain" xlink:label="EquityComponentDomain" xlink:title="EquityComponentDomain" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.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/2022/elts/us-gaap-2022.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>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="FairValueNetAssetLiabilityAbstract" xlink:to="us-gaap_FairValueNetAssetLiabilityAbstract_lbl" xlink:title="label: FairValueNetAssetLiabilityAbstract to us-gaap_FairValueNetAssetLiabilityAbstract_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_FairValueNetAssetLiabilityAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_FairValueNetAssetLiabilityAbstract_lbl1" xml:lang="en-US" id="us-gaap_FairValueNetAssetLiabilityAbstract_lbl1">Fair Value, Net Asset (Liability) [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="FairValueNetAssetLiabilityAbstract" xlink:to="us-gaap_FairValueNetAssetLiabilityAbstract_lbl1" xlink:title="label: FairValueNetAssetLiabilityAbstract to us-gaap_FairValueNetAssetLiabilityAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FairValueByMeasurementFrequencyAxis" xlink:label="FairValueByMeasurementFrequencyAxis" xlink:title="FairValueByMeasurementFrequencyAxis" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems" xlink:label="FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems" xlink:title="FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FairValueDisclosuresAbstract" xlink:label="FairValueDisclosuresAbstract" xlink:title="FairValueDisclosuresAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_FairValueDisclosuresAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_FairValueDisclosuresAbstract_lbl" xml:lang="en-US" id="us-gaap_FairValueDisclosuresAbstract_lbl">Fair Value Measurements [Abstract]</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_FairValueInputsLevel1Member_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_FairValueInputsLevel1Member_lbl" xml:lang="en-US" id="us-gaap_FairValueInputsLevel1Member_lbl">Quoted Prices in Active Markets (Level 1) [Member]</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_FairValueInputsLevel1Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_FairValueInputsLevel1Member_lbl1" xml:lang="en-US" id="us-gaap_FairValueInputsLevel1Member_lbl1">Fair Value, Inputs, Level 1 [Member]</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_FairValueInputsLevel2Member" xlink:label="FairValueInputsLevel2Member" xlink:title="FairValueInputsLevel2Member" />
    <link:label xlink:type="resource" xlink:label="us-gaap_FairValueInputsLevel2Member_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_FairValueInputsLevel2Member_lbl" xml:lang="en-US" id="us-gaap_FairValueInputsLevel2Member_lbl">Significant Other Observable Inputs (Level 2) [Member]</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_FairValueInputsLevel2Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_FairValueInputsLevel2Member_lbl1" xml:lang="en-US" id="us-gaap_FairValueInputsLevel2Member_lbl1">Fair Value, Inputs, Level 2 [Member]</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.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>
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    <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/2022/elts/us-gaap-2022.xsd#us-gaap_InventoryLineItems" xlink:label="InventoryLineItems" xlink:title="InventoryLineItems" />
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    <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/2022/elts/us-gaap-2022.xsd#us-gaap_InventoryCurrentTable" xlink:label="InventoryCurrentTable" xlink:title="InventoryCurrentTable" />
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    <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" />
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    <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>
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    <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" />
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    <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" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LegalMattersAndContingenciesTextBlock" xlink:label="LegalMattersAndContingenciesTextBlock" xlink:title="LegalMattersAndContingenciesTextBlock" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LegalMattersAndContingenciesTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_LegalMattersAndContingenciesTextBlock_lbl" xml:lang="en-US" id="us-gaap_LegalMattersAndContingenciesTextBlock_lbl">Legal Proceedings</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LegalMattersAndContingenciesTextBlock" xlink:to="us-gaap_LegalMattersAndContingenciesTextBlock_lbl" xlink:title="label: LegalMattersAndContingenciesTextBlock to us-gaap_LegalMattersAndContingenciesTextBlock_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LegalMattersAndContingenciesTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LegalMattersAndContingenciesTextBlock_lbl1" xml:lang="en-US" id="us-gaap_LegalMattersAndContingenciesTextBlock_lbl1">Legal Matters and Contingencies [Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LegalMattersAndContingenciesTextBlock" xlink:to="us-gaap_LegalMattersAndContingenciesTextBlock_lbl1" xlink:title="label: LegalMattersAndContingenciesTextBlock to us-gaap_LegalMattersAndContingenciesTextBlock_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LiabilitiesAndStockholdersEquityAbstract" xlink:label="LiabilitiesAndStockholdersEquityAbstract" xlink:title="LiabilitiesAndStockholdersEquityAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LiabilitiesAndStockholdersEquityAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_LiabilitiesAndStockholdersEquityAbstract_lbl" xml:lang="en-US" id="us-gaap_LiabilitiesAndStockholdersEquityAbstract_lbl">LIABILITIES AND STOCKHOLDERS' EQUITY</link:label>
    <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" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LiabilitiesAndStockholdersEquityAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LiabilitiesAndStockholdersEquityAbstract_lbl1" xml:lang="en-US" id="us-gaap_LiabilitiesAndStockholdersEquityAbstract_lbl1">Liabilities and Equity [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LiabilitiesAndStockholdersEquityAbstract" xlink:to="us-gaap_LiabilitiesAndStockholdersEquityAbstract_lbl1" xlink:title="label: LiabilitiesAndStockholdersEquityAbstract to us-gaap_LiabilitiesAndStockholdersEquityAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LiabilitiesAndStockholdersEquity" xlink:label="LiabilitiesAndStockholdersEquity" xlink:title="LiabilitiesAndStockholdersEquity" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LiabilitiesAndStockholdersEquity_lbl" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_LiabilitiesAndStockholdersEquity_lbl" xml:lang="en-US" id="us-gaap_LiabilitiesAndStockholdersEquity_lbl">Total liabilities and stockholders' equity</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LiabilitiesAndStockholdersEquity" xlink:to="us-gaap_LiabilitiesAndStockholdersEquity_lbl" xlink:title="label: LiabilitiesAndStockholdersEquity to us-gaap_LiabilitiesAndStockholdersEquity_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LiabilitiesAndStockholdersEquity_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LiabilitiesAndStockholdersEquity_lbl1" xml:lang="en-US" id="us-gaap_LiabilitiesAndStockholdersEquity_lbl1">Liabilities and Equity</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LiabilitiesAndStockholdersEquity" xlink:to="us-gaap_LiabilitiesAndStockholdersEquity_lbl1" xlink:title="label: LiabilitiesAndStockholdersEquity to us-gaap_LiabilitiesAndStockholdersEquity_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_Liabilities" xlink:label="Liabilities" xlink:title="Liabilities" />
    <link:label xlink:type="resource" xlink:label="us-gaap_Liabilities_lbl" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_Liabilities_lbl" xml:lang="en-US" id="us-gaap_Liabilities_lbl">Total liabilities</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Liabilities" xlink:to="us-gaap_Liabilities_lbl" xlink:title="label: Liabilities to us-gaap_Liabilities_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_Liabilities_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_Liabilities_lbl1" xml:lang="en-US" id="us-gaap_Liabilities_lbl1">Liabilities</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="Liabilities" xlink:to="us-gaap_Liabilities_lbl1" xlink:title="label: Liabilities to us-gaap_Liabilities_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LiabilitiesCurrent" xlink:label="LiabilitiesCurrent" xlink:title="LiabilitiesCurrent" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LiabilitiesCurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_LiabilitiesCurrent_lbl" xml:lang="en-US" id="us-gaap_LiabilitiesCurrent_lbl">Total current liabilities</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LiabilitiesCurrent" xlink:to="us-gaap_LiabilitiesCurrent_lbl" xlink:title="label: LiabilitiesCurrent to us-gaap_LiabilitiesCurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LiabilitiesCurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LiabilitiesCurrent_lbl1" xml:lang="en-US" id="us-gaap_LiabilitiesCurrent_lbl1">Liabilities, Current</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LiabilitiesCurrent" xlink:to="us-gaap_LiabilitiesCurrent_lbl1" xlink:title="label: LiabilitiesCurrent to us-gaap_LiabilitiesCurrent_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LiabilitiesCurrentAbstract" xlink:label="LiabilitiesCurrentAbstract" xlink:title="LiabilitiesCurrentAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LiabilitiesCurrentAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_LiabilitiesCurrentAbstract_lbl" xml:lang="en-US" id="us-gaap_LiabilitiesCurrentAbstract_lbl">Current liabilities:</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LiabilitiesCurrentAbstract" xlink:to="us-gaap_LiabilitiesCurrentAbstract_lbl" xlink:title="label: LiabilitiesCurrentAbstract to us-gaap_LiabilitiesCurrentAbstract_lbl" />
    <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>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LiabilitiesCurrentAbstract" xlink:to="us-gaap_LiabilitiesCurrentAbstract_lbl1" xlink:title="label: LiabilitiesCurrentAbstract to us-gaap_LiabilitiesCurrentAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_LongTermLoansFromBank" xlink:label="LongTermLoansFromBank" xlink:title="LongTermLoansFromBank" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LongTermLoansFromBank_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LongTermLoansFromBank_lbl" xml:lang="en-US" id="us-gaap_LongTermLoansFromBank_lbl">Long-term mortgage debt</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermLoansFromBank" xlink:to="us-gaap_LongTermLoansFromBank_lbl" xlink:title="label: LongTermLoansFromBank to us-gaap_LongTermLoansFromBank_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:label="NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:title="NetCashProvidedByUsedInFinancingActivitiesAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract_lbl" xml:lang="en-US" id="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract_lbl">Financing activities:</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:to="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract_lbl" xlink:title="label: NetCashProvidedByUsedInFinancingActivitiesAbstract to us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract_lbl1" xml:lang="en-US" id="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract_lbl1">Net Cash Provided by (Used in) Financing Activities [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:to="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract_lbl1" xlink:title="label: NetCashProvidedByUsedInFinancingActivitiesAbstract to us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:label="NetCashProvidedByUsedInOperatingActivities" xlink:title="NetCashProvidedByUsedInOperatingActivities" />
    <link:label xlink:type="resource" xlink:label="us-gaap_NetCashProvidedByUsedInOperatingActivities_lbl" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_NetCashProvidedByUsedInOperatingActivities_lbl" xml:lang="en-US" id="us-gaap_NetCashProvidedByUsedInOperatingActivities_lbl">Net cash used in operating activities</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NetCashProvidedByUsedInOperatingActivities" xlink:to="us-gaap_NetCashProvidedByUsedInOperatingActivities_lbl" xlink:title="label: NetCashProvidedByUsedInOperatingActivities to us-gaap_NetCashProvidedByUsedInOperatingActivities_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_NetCashProvidedByUsedInOperatingActivities_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_NetCashProvidedByUsedInOperatingActivities_lbl1" xml:lang="en-US" id="us-gaap_NetCashProvidedByUsedInOperatingActivities_lbl1">Net Cash Provided by (Used in) Operating Activities</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NetCashProvidedByUsedInOperatingActivities" xlink:to="us-gaap_NetCashProvidedByUsedInOperatingActivities_lbl1" xlink:title="label: NetCashProvidedByUsedInOperatingActivities to us-gaap_NetCashProvidedByUsedInOperatingActivities_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_NetCashProvidedByUsedInInvestingActivities" xlink:label="NetCashProvidedByUsedInInvestingActivities" xlink:title="NetCashProvidedByUsedInInvestingActivities" />
    <link:label xlink:type="resource" xlink:label="us-gaap_NetCashProvidedByUsedInInvestingActivities_lbl" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_NetCashProvidedByUsedInInvestingActivities_lbl" xml:lang="en-US" id="us-gaap_NetCashProvidedByUsedInInvestingActivities_lbl">Net cash used in investing activities</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_NetCashProvidedByUsedInInvestingActivities_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_NetCashProvidedByUsedInInvestingActivities_lbl1" xml:lang="en-US" id="us-gaap_NetCashProvidedByUsedInInvestingActivities_lbl1">Net Cash Provided by (Used in) Investing Activities</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NetCashProvidedByUsedInInvestingActivities" xlink:to="us-gaap_NetCashProvidedByUsedInInvestingActivities_lbl1" xlink:title="label: NetCashProvidedByUsedInInvestingActivities to us-gaap_NetCashProvidedByUsedInInvestingActivities_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:label="NetCashProvidedByUsedInFinancingActivities" xlink:title="NetCashProvidedByUsedInFinancingActivities" />
    <link:label xlink:type="resource" xlink:label="us-gaap_NetCashProvidedByUsedInFinancingActivities_lbl" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_NetCashProvidedByUsedInFinancingActivities_lbl" xml:lang="en-US" id="us-gaap_NetCashProvidedByUsedInFinancingActivities_lbl">Net cash provided by (used in) financing activities</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NetCashProvidedByUsedInFinancingActivities" xlink:to="us-gaap_NetCashProvidedByUsedInFinancingActivities_lbl" xlink:title="label: NetCashProvidedByUsedInFinancingActivities to us-gaap_NetCashProvidedByUsedInFinancingActivities_lbl" />
    <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>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NetCashProvidedByUsedInFinancingActivities" xlink:to="us-gaap_NetCashProvidedByUsedInFinancingActivities_lbl1" xlink:title="label: NetCashProvidedByUsedInFinancingActivities to us-gaap_NetCashProvidedByUsedInFinancingActivities_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract" xlink:label="NetCashProvidedByUsedInInvestingActivitiesAbstract" xlink:title="NetCashProvidedByUsedInInvestingActivitiesAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract_lbl" xml:lang="en-US" id="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract_lbl">Investing activities:</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract_lbl1" xml:lang="en-US" id="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract_lbl1">Net Cash Provided by (Used in) Investing Activities [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NetCashProvidedByUsedInInvestingActivitiesAbstract" xlink:to="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract_lbl1" xlink:title="label: NetCashProvidedByUsedInInvestingActivitiesAbstract to us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract" xlink:label="NetCashProvidedByUsedInOperatingActivitiesAbstract" xlink:title="NetCashProvidedByUsedInOperatingActivitiesAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract_lbl" xml:lang="en-US" id="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract_lbl">Operating activities:</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract_lbl1" xml:lang="en-US" id="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract_lbl1">Net Cash Provided by (Used in) Operating Activities [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NetCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract_lbl1" xlink:title="label: NetCashProvidedByUsedInOperatingActivitiesAbstract to us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_NetIncomeLoss" xlink:label="NetIncomeLoss" xlink:title="NetIncomeLoss" />
    <link:label xlink:type="resource" xlink:label="us-gaap_NetIncomeLoss_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_NetIncomeLoss_lbl" xml:lang="en-US" id="us-gaap_NetIncomeLoss_lbl">Net loss</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NetIncomeLoss" xlink:to="us-gaap_NetIncomeLoss_lbl" xlink:title="label: NetIncomeLoss to us-gaap_NetIncomeLoss_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_NetIncomeLoss_lbl1" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_NetIncomeLoss_lbl1" xml:lang="en-US" id="us-gaap_NetIncomeLoss_lbl1">Net loss</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NetIncomeLoss" xlink:to="us-gaap_NetIncomeLoss_lbl1" xlink:title="label: NetIncomeLoss to us-gaap_NetIncomeLoss_lbl1" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NetIncomeLoss" xlink:to="us-gaap_NetIncomeLoss_lbl2" xlink:title="label: NetIncomeLoss to us-gaap_NetIncomeLoss_lbl2" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_NewAccountingPronouncementsPolicyPolicyTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="us-gaap_NewAccountingPronouncementsPolicyPolicyTextBlock_lbl" xml:lang="en-US" id="us-gaap_NewAccountingPronouncementsPolicyPolicyTextBlock_lbl">Recently Adopted Accounting Standards</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NewAccountingPronouncementsPolicyPolicyTextBlock" xlink:to="us-gaap_NewAccountingPronouncementsPolicyPolicyTextBlock_lbl" xlink:title="label: NewAccountingPronouncementsPolicyPolicyTextBlock to us-gaap_NewAccountingPronouncementsPolicyPolicyTextBlock_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_NewAccountingPronouncementsPolicyPolicyTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_NewAccountingPronouncementsPolicyPolicyTextBlock_lbl1" xml:lang="en-US" id="us-gaap_NewAccountingPronouncementsPolicyPolicyTextBlock_lbl1">New Accounting Pronouncements, Policy [Policy Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NewAccountingPronouncementsPolicyPolicyTextBlock" xlink:to="us-gaap_NewAccountingPronouncementsPolicyPolicyTextBlock_lbl1" xlink:title="label: NewAccountingPronouncementsPolicyPolicyTextBlock to us-gaap_NewAccountingPronouncementsPolicyPolicyTextBlock_lbl1" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_NonoperatingIncomeExpenseAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_NonoperatingIncomeExpenseAbstract_lbl" xml:lang="en-US" id="us-gaap_NonoperatingIncomeExpenseAbstract_lbl">Other income (expense):</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NonoperatingIncomeExpenseAbstract" xlink:to="us-gaap_NonoperatingIncomeExpenseAbstract_lbl" xlink:title="label: NonoperatingIncomeExpenseAbstract to us-gaap_NonoperatingIncomeExpenseAbstract_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_NonoperatingIncomeExpenseAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_NonoperatingIncomeExpenseAbstract_lbl1" xml:lang="en-US" id="us-gaap_NonoperatingIncomeExpenseAbstract_lbl1">Nonoperating Income (Expense) [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NonoperatingIncomeExpenseAbstract" xlink:to="us-gaap_NonoperatingIncomeExpenseAbstract_lbl1" xlink:title="label: NonoperatingIncomeExpenseAbstract to us-gaap_NonoperatingIncomeExpenseAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_NotesPayableFairValueDisclosure" xlink:label="NotesPayableFairValueDisclosure" xlink:title="NotesPayableFairValueDisclosure" />
    <link:label xlink:type="resource" xlink:label="us-gaap_NotesPayableFairValueDisclosure_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_NotesPayableFairValueDisclosure_lbl" xml:lang="en-US" id="us-gaap_NotesPayableFairValueDisclosure_lbl">Convertible notes</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NotesPayableFairValueDisclosure" xlink:to="us-gaap_NotesPayableFairValueDisclosure_lbl" xlink:title="label: NotesPayableFairValueDisclosure to us-gaap_NotesPayableFairValueDisclosure_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_NotesPayableFairValueDisclosure_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_NotesPayableFairValueDisclosure_lbl1" xml:lang="en-US" id="us-gaap_NotesPayableFairValueDisclosure_lbl1">Notes Payable, Fair Value Disclosure</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NotesPayableFairValueDisclosure" xlink:to="us-gaap_NotesPayableFairValueDisclosure_lbl1" xlink:title="label: NotesPayableFairValueDisclosure to us-gaap_NotesPayableFairValueDisclosure_lbl1" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_NumberOfOperatingSegments_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_NumberOfOperatingSegments_lbl" xml:lang="en-US" id="us-gaap_NumberOfOperatingSegments_lbl">Number of operating segments</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfOperatingSegments" xlink:to="us-gaap_NumberOfOperatingSegments_lbl" xlink:title="label: NumberOfOperatingSegments to us-gaap_NumberOfOperatingSegments_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OperatingLeaseLiabilityNoncurrent" xlink:label="OperatingLeaseLiabilityNoncurrent" xlink:title="OperatingLeaseLiabilityNoncurrent" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingLeaseLiabilityNoncurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OperatingLeaseLiabilityNoncurrent_lbl" xml:lang="en-US" id="us-gaap_OperatingLeaseLiabilityNoncurrent_lbl">Long-term lease liabilities</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingLeaseLiabilityNoncurrent" xlink:to="us-gaap_OperatingLeaseLiabilityNoncurrent_lbl" xlink:title="label: OperatingLeaseLiabilityNoncurrent to us-gaap_OperatingLeaseLiabilityNoncurrent_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense" xlink:label="OperatingLeaseRightOfUseAssetAmortizationExpense" xlink:title="OperatingLeaseRightOfUseAssetAmortizationExpense" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense_lbl" xml:lang="en-US" id="us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense_lbl">Amortization of right-of-use operating lease assets</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingLeaseRightOfUseAssetAmortizationExpense" xlink:to="us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense_lbl" xlink:title="label: OperatingLeaseRightOfUseAssetAmortizationExpense to us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense_lbl1" xml:lang="en-US" id="us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense_lbl1">Operating Lease, Right-of-Use Asset, Amortization Expense</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingLeaseRightOfUseAssetAmortizationExpense" xlink:to="us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense_lbl1" xlink:title="label: OperatingLeaseRightOfUseAssetAmortizationExpense to us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense_lbl1" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingLeaseRightOfUseAsset_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OperatingLeaseRightOfUseAsset_lbl" xml:lang="en-US" id="us-gaap_OperatingLeaseRightOfUseAsset_lbl">Right-of-use assets</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OperatingIncomeLoss" xlink:label="OperatingIncomeLoss" xlink:title="OperatingIncomeLoss" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingIncomeLoss_lbl" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_OperatingIncomeLoss_lbl" xml:lang="en-US" id="us-gaap_OperatingIncomeLoss_lbl">Loss from operations</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingIncomeLoss" xlink:to="us-gaap_OperatingIncomeLoss_lbl" xlink:title="label: OperatingIncomeLoss to us-gaap_OperatingIncomeLoss_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingIncomeLoss_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OperatingIncomeLoss_lbl1" xml:lang="en-US" id="us-gaap_OperatingIncomeLoss_lbl1">Operating Income (Loss)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingIncomeLoss" xlink:to="us-gaap_OperatingIncomeLoss_lbl1" xlink:title="label: OperatingIncomeLoss to us-gaap_OperatingIncomeLoss_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTextBlock" xlink:label="OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTextBlock" xlink:title="OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTextBlock" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTextBlock_lbl" xml:lang="en-US" id="us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTextBlock_lbl">Organization and Basis of Presentation</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTextBlock" xlink:to="us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTextBlock_lbl" xlink:title="label: OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTextBlock to us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTextBlock_lbl" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTextBlock" xlink:to="us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTextBlock_lbl1" xlink:title="label: OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTextBlock to us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTextBlock_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsAbstract" xlink:label="OrganizationConsolidationAndPresentationOfFinancialStatementsAbstract" xlink:title="OrganizationConsolidationAndPresentationOfFinancialStatementsAbstract" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OtherNoncurrentLiabilitiesTableTextBlock" xlink:to="us-gaap_OtherNoncurrentLiabilitiesTableTextBlock_lbl" xlink:title="label: OtherNoncurrentLiabilitiesTableTextBlock to us-gaap_OtherNoncurrentLiabilitiesTableTextBlock_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OtherNoncurrentLiabilitiesTableTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OtherNoncurrentLiabilitiesTableTextBlock_lbl1" xml:lang="en-US" id="us-gaap_OtherNoncurrentLiabilitiesTableTextBlock_lbl1">Other Noncurrent Liabilities [Table Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OtherNoncurrentLiabilitiesTableTextBlock" xlink:to="us-gaap_OtherNoncurrentLiabilitiesTableTextBlock_lbl1" xlink:title="label: OtherNoncurrentLiabilitiesTableTextBlock to us-gaap_OtherNoncurrentLiabilitiesTableTextBlock_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OtherCurrentAssetsMember" xlink:label="OtherCurrentAssetsMember" xlink:title="OtherCurrentAssetsMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OtherCurrentAssetsMember_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OtherCurrentAssetsMember_lbl" xml:lang="en-US" id="us-gaap_OtherCurrentAssetsMember_lbl">Other Current Assets [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OtherCurrentAssetsMember" xlink:to="us-gaap_OtherCurrentAssetsMember_lbl" xlink:title="label: OtherCurrentAssetsMember to us-gaap_OtherCurrentAssetsMember_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OtherLiabilitiesDisclosureAbstract" xlink:label="OtherLiabilitiesDisclosureAbstract" xlink:title="OtherLiabilitiesDisclosureAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OtherLiabilitiesDisclosureAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OtherLiabilitiesDisclosureAbstract_lbl" xml:lang="en-US" id="us-gaap_OtherLiabilitiesDisclosureAbstract_lbl">Liability Related to Sale of Future Royalties [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OtherLiabilitiesDisclosureAbstract" xlink:to="us-gaap_OtherLiabilitiesDisclosureAbstract_lbl" xlink:title="label: OtherLiabilitiesDisclosureAbstract to us-gaap_OtherLiabilitiesDisclosureAbstract_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OtherAssetsNoncurrent" xlink:label="OtherAssetsNoncurrent" xlink:title="OtherAssetsNoncurrent" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OtherAssetsNoncurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_OtherAssetsNoncurrent_lbl" xml:lang="en-US" id="us-gaap_OtherAssetsNoncurrent_lbl">Deposits and other assets</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_OtherAssetsNoncurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OtherAssetsNoncurrent_lbl1" xml:lang="en-US" id="us-gaap_OtherAssetsNoncurrent_lbl1">Other Assets, Noncurrent</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OtherAssetsNoncurrent" xlink:to="us-gaap_OtherAssetsNoncurrent_lbl1" xlink:title="label: OtherAssetsNoncurrent to us-gaap_OtherAssetsNoncurrent_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OtherAssetsCurrent" xlink:label="OtherAssetsCurrent" xlink:title="OtherAssetsCurrent" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OtherAssetsCurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_OtherAssetsCurrent_lbl" xml:lang="en-US" id="us-gaap_OtherAssetsCurrent_lbl">Other current assets</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_OtherAssetsCurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OtherAssetsCurrent_lbl1" xml:lang="en-US" id="us-gaap_OtherAssetsCurrent_lbl1">Other Assets, Current</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_OtherDebtSecuritiesMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OtherDebtSecuritiesMember_lbl1" xml:lang="en-US" id="us-gaap_OtherDebtSecuritiesMember_lbl1">Other Debt Obligations [Member]</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_OtherLiabilitiesCurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OtherLiabilitiesCurrent_lbl" xml:lang="en-US" id="us-gaap_OtherLiabilitiesCurrent_lbl">Other current liabilities</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OtherLiabilitiesCurrent" xlink:to="us-gaap_OtherLiabilitiesCurrent_lbl" xlink:title="label: OtherLiabilitiesCurrent to us-gaap_OtherLiabilitiesCurrent_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OtherLiabilitiesDisclosureTextBlock" xlink:label="OtherLiabilitiesDisclosureTextBlock" xlink:title="OtherLiabilitiesDisclosureTextBlock" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OtherLiabilitiesDisclosureTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_OtherLiabilitiesDisclosureTextBlock_lbl" xml:lang="en-US" id="us-gaap_OtherLiabilitiesDisclosureTextBlock_lbl">Liability Related to Sale of Future Royalties</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OtherLiabilitiesDisclosureTextBlock" xlink:to="us-gaap_OtherLiabilitiesDisclosureTextBlock_lbl" xlink:title="label: OtherLiabilitiesDisclosureTextBlock to us-gaap_OtherLiabilitiesDisclosureTextBlock_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OtherLiabilitiesDisclosureTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OtherLiabilitiesDisclosureTextBlock_lbl1" xml:lang="en-US" id="us-gaap_OtherLiabilitiesDisclosureTextBlock_lbl1">Other Liabilities Disclosure [Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OtherLiabilitiesDisclosureTextBlock" xlink:to="us-gaap_OtherLiabilitiesDisclosureTextBlock_lbl1" xlink:title="label: OtherLiabilitiesDisclosureTextBlock to us-gaap_OtherLiabilitiesDisclosureTextBlock_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OtherLiabilitiesNoncurrent" xlink:label="OtherLiabilitiesNoncurrent" xlink:title="OtherLiabilitiesNoncurrent" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OtherLiabilitiesNoncurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_OtherLiabilitiesNoncurrent_lbl" xml:lang="en-US" id="us-gaap_OtherLiabilitiesNoncurrent_lbl">Long-term obligations</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OtherLiabilitiesNoncurrent" xlink:to="us-gaap_OtherLiabilitiesNoncurrent_lbl" xlink:title="label: OtherLiabilitiesNoncurrent to us-gaap_OtherLiabilitiesNoncurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OtherLiabilitiesNoncurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OtherLiabilitiesNoncurrent_lbl1" xml:lang="en-US" id="us-gaap_OtherLiabilitiesNoncurrent_lbl1">Other Liabilities, Noncurrent</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OtherLiabilitiesNoncurrent" xlink:to="us-gaap_OtherLiabilitiesNoncurrent_lbl1" xlink:title="label: OtherLiabilitiesNoncurrent to us-gaap_OtherLiabilitiesNoncurrent_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OtherNonoperatingIncomeExpense" xlink:label="OtherNonoperatingIncomeExpense" xlink:title="OtherNonoperatingIncomeExpense" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OtherNonoperatingIncomeExpense_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_OtherNonoperatingIncomeExpense_lbl" xml:lang="en-US" id="us-gaap_OtherNonoperatingIncomeExpense_lbl">Other income</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OtherNonoperatingIncomeExpense" xlink:to="us-gaap_OtherNonoperatingIncomeExpense_lbl" xlink:title="label: OtherNonoperatingIncomeExpense to us-gaap_OtherNonoperatingIncomeExpense_lbl" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OtherNonoperatingIncomeExpense" xlink:to="us-gaap_OtherNonoperatingIncomeExpense_lbl1" xlink:title="label: OtherNonoperatingIncomeExpense to us-gaap_OtherNonoperatingIncomeExpense_lbl1" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_OtherAccruedLiabilitiesCurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_OtherAccruedLiabilitiesCurrent_lbl" xml:lang="en-US" id="us-gaap_OtherAccruedLiabilitiesCurrent_lbl">Other miscellaneous expenses</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_OtherAccruedLiabilitiesCurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OtherAccruedLiabilitiesCurrent_lbl1" xml:lang="en-US" id="us-gaap_OtherAccruedLiabilitiesCurrent_lbl1">Other Accrued Liabilities, Current</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OtherAccruedLiabilitiesCurrent" xlink:to="us-gaap_OtherAccruedLiabilitiesCurrent_lbl1" xlink:title="label: OtherAccruedLiabilitiesCurrent to us-gaap_OtherAccruedLiabilitiesCurrent_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" xlink:label="OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" xlink:title="OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PaymentsForHedgeFinancingActivities" xlink:label="PaymentsForHedgeFinancingActivities" xlink:title="PaymentsForHedgeFinancingActivities" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_PaymentsForHedgeFinancingActivities_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_PaymentsForHedgeFinancingActivities_lbl1" xml:lang="en-US" id="us-gaap_PaymentsForHedgeFinancingActivities_lbl1">Payments for Hedge, Financing Activities</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PaymentsRelatedToTaxWithholdingForShareBasedCompensation" xlink:label="PaymentsRelatedToTaxWithholdingForShareBasedCompensation" xlink:title="PaymentsRelatedToTaxWithholdingForShareBasedCompensation" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_PaymentsRelatedToTaxWithholdingForShareBasedCompensation_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_PaymentsRelatedToTaxWithholdingForShareBasedCompensation_lbl1" xml:lang="en-US" id="us-gaap_PaymentsRelatedToTaxWithholdingForShareBasedCompensation_lbl1">Payment, Tax Withholding, Share-Based Payment Arrangement</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentsRelatedToTaxWithholdingForShareBasedCompensation" xlink:to="us-gaap_PaymentsRelatedToTaxWithholdingForShareBasedCompensation_lbl1" xlink:title="label: PaymentsRelatedToTaxWithholdingForShareBasedCompensation to us-gaap_PaymentsRelatedToTaxWithholdingForShareBasedCompensation_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.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/negatedTerseLabel" 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:label xlink:type="resource" xlink:label="us-gaap_PaymentsToAcquireIntangibleAssets_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_PaymentsToAcquireIntangibleAssets_lbl1" xml:lang="en-US" id="us-gaap_PaymentsToAcquireIntangibleAssets_lbl1">Payments to Acquire Intangible Assets</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PaymentsToAcquireAvailableForSaleSecuritiesDebt" xlink:label="PaymentsToAcquireAvailableForSaleSecuritiesDebt" xlink:title="PaymentsToAcquireAvailableForSaleSecuritiesDebt" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_PaymentsToAcquirePropertyPlantAndEquipment_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_PaymentsToAcquirePropertyPlantAndEquipment_lbl1" xml:lang="en-US" id="us-gaap_PaymentsToAcquirePropertyPlantAndEquipment_lbl1">Payments to Acquire Property, Plant, and Equipment</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentsToAcquirePropertyPlantAndEquipment" xlink:to="us-gaap_PaymentsToAcquirePropertyPlantAndEquipment_lbl1" xlink:title="label: PaymentsToAcquirePropertyPlantAndEquipment to us-gaap_PaymentsToAcquirePropertyPlantAndEquipment_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PerformanceSharesMember" xlink:label="PerformanceSharesMember" xlink:title="PerformanceSharesMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_PerformanceSharesMember_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_PerformanceSharesMember_lbl" xml:lang="en-US" id="us-gaap_PerformanceSharesMember_lbl">PRSUs [Member]</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_PerformanceSharesMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_PerformanceSharesMember_lbl1" xml:lang="en-US" id="us-gaap_PerformanceSharesMember_lbl1">Performance Shares [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PerformanceSharesMember" xlink:to="us-gaap_PerformanceSharesMember_lbl1" xlink:title="label: PerformanceSharesMember to us-gaap_PerformanceSharesMember_lbl1" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ProductMember" xlink:label="ProductMember" xlink:title="ProductMember" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PropertyPlantAndEquipmentNet" xlink:label="PropertyPlantAndEquipmentNet" xlink:title="PropertyPlantAndEquipmentNet" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PublicUtilitiesInventoryAxis" xlink:label="PublicUtilitiesInventoryAxis" xlink:title="PublicUtilitiesInventoryAxis" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PublicUtilitiesInventoryAxis" xlink:to="us-gaap_PublicUtilitiesInventoryAxis_lbl" xlink:title="label: PublicUtilitiesInventoryAxis to us-gaap_PublicUtilitiesInventoryAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_PublicUtilitiesInventoryTypeDomain" xlink:label="PublicUtilitiesInventoryTypeDomain" xlink:title="PublicUtilitiesInventoryTypeDomain" />
    <link:label xlink:type="resource" xlink:label="us-gaap_PublicUtilitiesInventoryTypeDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_PublicUtilitiesInventoryTypeDomain_lbl" xml:lang="en-US" id="us-gaap_PublicUtilitiesInventoryTypeDomain_lbl">Inventory [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PublicUtilitiesInventoryTypeDomain" xlink:to="us-gaap_PublicUtilitiesInventoryTypeDomain_lbl" xlink:title="label: PublicUtilitiesInventoryTypeDomain to us-gaap_PublicUtilitiesInventoryTypeDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RealizedInvestmentGainsLosses" xlink:label="RealizedInvestmentGainsLosses" xlink:title="RealizedInvestmentGainsLosses" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_RepaymentsOfConvertibleDebt" xlink:label="RepaymentsOfConvertibleDebt" xlink:title="RepaymentsOfConvertibleDebt" />
    <link:label xlink:type="resource" xlink:label="us-gaap_RepaymentsOfConvertibleDebt_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_RepaymentsOfConvertibleDebt_lbl" xml:lang="en-US" id="us-gaap_RepaymentsOfConvertibleDebt_lbl">Repurchase of convertible notes</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_RepaymentsOfConvertibleDebt_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_RepaymentsOfConvertibleDebt_lbl1" xml:lang="en-US" id="us-gaap_RepaymentsOfConvertibleDebt_lbl1">Repayments of Convertible Debt</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1" xlink:label="SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1" xlink:title="SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ScheduleOfShareBasedPaymentAwardEmployeeStockPurchasePlanValuationAssumptionsTableTextBlock" xlink:to="us-gaap_ScheduleOfShareBasedPaymentAwardEmployeeStockPurchasePlanValuationAssumptionsTableTextBlock_lbl" xlink:title="label: ScheduleOfShareBasedPaymentAwardEmployeeStockPurchasePlanValuationAssumptionsTableTextBlock to us-gaap_ScheduleOfShareBasedPaymentAwardEmployeeStockPurchasePlanValuationAssumptionsTableTextBlock_lbl" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ScheduleOfTemporaryImpairmentLossesInvestmentsTableTextBlock" xlink:label="ScheduleOfTemporaryImpairmentLossesInvestmentsTableTextBlock" xlink:title="ScheduleOfTemporaryImpairmentLossesInvestmentsTableTextBlock" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ScheduleOfTemporaryImpairmentLossesInvestmentsTableTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_ScheduleOfTemporaryImpairmentLossesInvestmentsTableTextBlock_lbl" xml:lang="en-US" id="us-gaap_ScheduleOfTemporaryImpairmentLossesInvestmentsTableTextBlock_lbl">Temporarily Impaired Investments</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_ScheduleOfTemporaryImpairmentLossesInvestmentsTableTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ScheduleOfTemporaryImpairmentLossesInvestmentsTableTextBlock_lbl1" xml:lang="en-US" id="us-gaap_ScheduleOfTemporaryImpairmentLossesInvestmentsTableTextBlock_lbl1">Schedule of Temporary Impairment Losses, Investments [Table Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ScheduleOfTemporaryImpairmentLossesInvestmentsTableTextBlock" xlink:to="us-gaap_ScheduleOfTemporaryImpairmentLossesInvestmentsTableTextBlock_lbl1" xlink:title="label: ScheduleOfTemporaryImpairmentLossesInvestmentsTableTextBlock to us-gaap_ScheduleOfTemporaryImpairmentLossesInvestmentsTableTextBlock_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ScheduleOfShareBasedPaymentAwardStockOptionsValuationAssumptionsTableTextBlock" xlink:label="ScheduleOfShareBasedPaymentAwardStockOptionsValuationAssumptionsTableTextBlock" xlink:title="ScheduleOfShareBasedPaymentAwardStockOptionsValuationAssumptionsTableTextBlock" />
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ScheduleOfCollaborativeArrangementsAndNoncollaborativeArrangementTransactionsTable" xlink:label="ScheduleOfCollaborativeArrangementsAndNoncollaborativeArrangementTransactionsTable" xlink:title="ScheduleOfCollaborativeArrangementsAndNoncollaborativeArrangementTransactionsTable" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable_lbl" xml:lang="en-US" id="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable_lbl">Schedule of Share-based Compensation Arrangements by Share-based Payment Award [Table]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:to="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable_lbl" xlink:title="label: ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable to us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock" xlink:label="SchedulesOfConcentrationOfRiskByRiskFactorTextBlock" xlink:title="SchedulesOfConcentrationOfRiskByRiskFactorTextBlock" />
    <link:label xlink:type="resource" xlink:label="us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock_lbl" xml:lang="en-US" id="us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock_lbl">Revenue from Collaborative Relationship</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SchedulesOfConcentrationOfRiskByRiskFactorTextBlock" xlink:to="us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock_lbl" xlink:title="label: SchedulesOfConcentrationOfRiskByRiskFactorTextBlock to us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock_lbl1" xml:lang="en-US" id="us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock_lbl1">Schedules of Concentration of Risk, by Risk Factor [Table Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SchedulesOfConcentrationOfRiskByRiskFactorTextBlock" xlink:to="us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock_lbl1" xlink:title="label: SchedulesOfConcentrationOfRiskByRiskFactorTextBlock to us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SegmentReportingPolicyPolicyTextBlock" xlink:label="SegmentReportingPolicyPolicyTextBlock" xlink:title="SegmentReportingPolicyPolicyTextBlock" />
    <link:label xlink:type="resource" xlink:label="us-gaap_SegmentReportingPolicyPolicyTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_SegmentReportingPolicyPolicyTextBlock_lbl" xml:lang="en-US" id="us-gaap_SegmentReportingPolicyPolicyTextBlock_lbl">Segment Information</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SegmentReportingPolicyPolicyTextBlock" xlink:to="us-gaap_SegmentReportingPolicyPolicyTextBlock_lbl" xlink:title="label: SegmentReportingPolicyPolicyTextBlock to us-gaap_SegmentReportingPolicyPolicyTextBlock_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_SegmentReportingPolicyPolicyTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_SegmentReportingPolicyPolicyTextBlock_lbl1" xml:lang="en-US" id="us-gaap_SegmentReportingPolicyPolicyTextBlock_lbl1">Segment Reporting, Policy [Policy Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SegmentReportingPolicyPolicyTextBlock" xlink:to="us-gaap_SegmentReportingPolicyPolicyTextBlock_lbl1" xlink:title="label: SegmentReportingPolicyPolicyTextBlock to us-gaap_SegmentReportingPolicyPolicyTextBlock_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SellingGeneralAndAdministrativeExpensesMember" xlink:label="SellingGeneralAndAdministrativeExpensesMember" xlink:title="SellingGeneralAndAdministrativeExpensesMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_SellingGeneralAndAdministrativeExpensesMember_lbl" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="us-gaap_SellingGeneralAndAdministrativeExpensesMember_lbl" xml:lang="en-US" id="us-gaap_SellingGeneralAndAdministrativeExpensesMember_lbl">Selling, General and Administrative Expense [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SellingGeneralAndAdministrativeExpensesMember" xlink:to="us-gaap_SellingGeneralAndAdministrativeExpensesMember_lbl" xlink:title="label: SellingGeneralAndAdministrativeExpensesMember to us-gaap_SellingGeneralAndAdministrativeExpensesMember_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_SellingGeneralAndAdministrativeExpensesMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_SellingGeneralAndAdministrativeExpensesMember_lbl1" xml:lang="en-US" id="us-gaap_SellingGeneralAndAdministrativeExpensesMember_lbl1">Selling, General and Administrative Expenses [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SellingGeneralAndAdministrativeExpensesMember" xlink:to="us-gaap_SellingGeneralAndAdministrativeExpensesMember_lbl1" xlink:title="label: SellingGeneralAndAdministrativeExpensesMember to us-gaap_SellingGeneralAndAdministrativeExpensesMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SellingGeneralAndAdministrativeExpense" xlink:label="SellingGeneralAndAdministrativeExpense" xlink:title="SellingGeneralAndAdministrativeExpense" />
    <link:label xlink:type="resource" xlink:label="us-gaap_SellingGeneralAndAdministrativeExpense_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_SellingGeneralAndAdministrativeExpense_lbl" xml:lang="en-US" id="us-gaap_SellingGeneralAndAdministrativeExpense_lbl">Selling, general and administrative</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SellingGeneralAndAdministrativeExpense" xlink:to="us-gaap_SellingGeneralAndAdministrativeExpense_lbl" xlink:title="label: SellingGeneralAndAdministrativeExpense to us-gaap_SellingGeneralAndAdministrativeExpense_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_SellingGeneralAndAdministrativeExpense_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_SellingGeneralAndAdministrativeExpense_lbl1" xml:lang="en-US" id="us-gaap_SellingGeneralAndAdministrativeExpense_lbl1">Selling, General and Administrative Expense</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SellingGeneralAndAdministrativeExpense" xlink:to="us-gaap_SellingGeneralAndAdministrativeExpense_lbl1" xlink:title="label: SellingGeneralAndAdministrativeExpense to us-gaap_SellingGeneralAndAdministrativeExpense_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedPaymentArrangementEmployeeMember" xlink:label="ShareBasedPaymentArrangementEmployeeMember" xlink:title="ShareBasedPaymentArrangementEmployeeMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedPaymentArrangementEmployeeMember_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_ShareBasedPaymentArrangementEmployeeMember_lbl" xml:lang="en-US" id="us-gaap_ShareBasedPaymentArrangementEmployeeMember_lbl">Employees [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedPaymentArrangementEmployeeMember" xlink:to="us-gaap_ShareBasedPaymentArrangementEmployeeMember_lbl" xlink:title="label: ShareBasedPaymentArrangementEmployeeMember to us-gaap_ShareBasedPaymentArrangementEmployeeMember_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedPaymentArrangementEmployeeMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ShareBasedPaymentArrangementEmployeeMember_lbl1" xml:lang="en-US" id="us-gaap_ShareBasedPaymentArrangementEmployeeMember_lbl1">Share-Based Payment Arrangement, Employee [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedPaymentArrangementEmployeeMember" xlink:to="us-gaap_ShareBasedPaymentArrangementEmployeeMember_lbl1" xlink:title="label: ShareBasedPaymentArrangementEmployeeMember to us-gaap_ShareBasedPaymentArrangementEmployeeMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" xlink:label="ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" xlink:title="ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1_lbl" xml:lang="en-US" id="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1_lbl">Vesting period</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1_lbl" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1 to us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1_lbl1" xml:lang="en-US" id="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1_lbl1">Share-Based Compensation Arrangement by Share-Based Payment Award, Award Vesting Period</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1_lbl1" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1 to us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationAwardTrancheThreeMember" xlink:label="ShareBasedCompensationAwardTrancheThreeMember" xlink:title="ShareBasedCompensationAwardTrancheThreeMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedCompensationAwardTrancheThreeMember_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ShareBasedCompensationAwardTrancheThreeMember_lbl" xml:lang="en-US" id="us-gaap_ShareBasedCompensationAwardTrancheThreeMember_lbl">Three-Year Period [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationAwardTrancheThreeMember" xlink:to="us-gaap_ShareBasedCompensationAwardTrancheThreeMember_lbl" xlink:title="label: ShareBasedCompensationAwardTrancheThreeMember to us-gaap_ShareBasedCompensationAwardTrancheThreeMember_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationAwardTrancheOneMember" xlink:label="ShareBasedCompensationAwardTrancheOneMember" xlink:title="ShareBasedCompensationAwardTrancheOneMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedCompensationAwardTrancheOneMember_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_ShareBasedCompensationAwardTrancheOneMember_lbl" xml:lang="en-US" id="us-gaap_ShareBasedCompensationAwardTrancheOneMember_lbl">One-Year Period [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationAwardTrancheOneMember" xlink:to="us-gaap_ShareBasedCompensationAwardTrancheOneMember_lbl" xlink:title="label: ShareBasedCompensationAwardTrancheOneMember to us-gaap_ShareBasedCompensationAwardTrancheOneMember_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedCompensationAwardTrancheOneMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ShareBasedCompensationAwardTrancheOneMember_lbl1" xml:lang="en-US" id="us-gaap_ShareBasedCompensationAwardTrancheOneMember_lbl1">Share-Based Payment Arrangement, Tranche One [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationAwardTrancheOneMember" xlink:to="us-gaap_ShareBasedCompensationAwardTrancheOneMember_lbl1" xlink:title="label: ShareBasedCompensationAwardTrancheOneMember to us-gaap_ShareBasedCompensationAwardTrancheOneMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationAwardTrancheTwoMember" xlink:label="ShareBasedCompensationAwardTrancheTwoMember" xlink:title="ShareBasedCompensationAwardTrancheTwoMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedCompensationAwardTrancheTwoMember_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ShareBasedCompensationAwardTrancheTwoMember_lbl" xml:lang="en-US" id="us-gaap_ShareBasedCompensationAwardTrancheTwoMember_lbl">Two-Year Period [Member]</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAdditionalGeneralDisclosuresAbstract" xlink:label="ShareBasedCompensationArrangementByShareBasedPaymentAwardAdditionalGeneralDisclosuresAbstract" xlink:title="ShareBasedCompensationArrangementByShareBasedPaymentAwardAdditionalGeneralDisclosuresAbstract" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAdditionalGeneralDisclosuresAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAdditionalGeneralDisclosuresAbstract_lbl1" xml:lang="en-US" id="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAdditionalGeneralDisclosuresAbstract_lbl1">Share-Based Compensation Arrangement by Share-Based Payment Award, Additional General Disclosures [Abstract]</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:label="ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:title="ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems_lbl" xml:lang="en-US" id="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems_lbl">Share-based Compensation Arrangement by Share-based Payment Award [Line Items]</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensation" xlink:label="ShareBasedCompensation" xlink:title="ShareBasedCompensation" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedCompensation_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_ShareBasedCompensation_lbl" xml:lang="en-US" id="us-gaap_ShareBasedCompensation_lbl">Stock-based compensation expense</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedCompensation_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ShareBasedCompensation_lbl1" xml:lang="en-US" id="us-gaap_ShareBasedCompensation_lbl1">Share-Based Payment Arrangement, Noncash Expense</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensation" xlink:to="us-gaap_ShareBasedCompensation_lbl1" xlink:title="label: ShareBasedCompensation to us-gaap_ShareBasedCompensation_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_ShareBasedCompensationAbstract" xlink:label="ShareBasedCompensationAbstract" xlink:title="ShareBasedCompensationAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedCompensationAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_ShareBasedCompensationAbstract_lbl" xml:lang="en-US" id="us-gaap_ShareBasedCompensationAbstract_lbl">Stock-based Compensation Expense [Abstract]</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_ShareBasedCompensationAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ShareBasedCompensationAbstract_lbl1" xml:lang="en-US" id="us-gaap_ShareBasedCompensationAbstract_lbl1">Share-Based Payment Arrangement, Noncash Expense [Abstract]</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.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:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StatementOfCashFlowsAbstract" xlink:label="StatementOfCashFlowsAbstract" xlink:title="StatementOfCashFlowsAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_StatementOfCashFlowsAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_StatementOfCashFlowsAbstract_lbl" xml:lang="en-US" id="us-gaap_StatementOfCashFlowsAbstract_lbl">CONSOLIDATED STATEMENTS OF CASH FLOWS [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StatementOfCashFlowsAbstract" xlink:to="us-gaap_StatementOfCashFlowsAbstract_lbl" xlink:title="label: StatementOfCashFlowsAbstract to us-gaap_StatementOfCashFlowsAbstract_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StatementTable" xlink:label="StatementTable" xlink:title="StatementTable" />
    <link:label xlink:type="resource" xlink:label="us-gaap_StatementTable_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_StatementTable_lbl" xml:lang="en-US" id="us-gaap_StatementTable_lbl">Statement [Table]</link:label>
    <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" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_StatementOfStockholdersEquityAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_StatementOfStockholdersEquityAbstract_lbl" xml:lang="en-US" id="us-gaap_StatementOfStockholdersEquityAbstract_lbl">CONSOLIDATED STATEMENTS OF STOCKHOLDERS' EQUITY [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StatementOfStockholdersEquityAbstract" xlink:to="us-gaap_StatementOfStockholdersEquityAbstract_lbl" xlink:title="label: StatementOfStockholdersEquityAbstract to us-gaap_StatementOfStockholdersEquityAbstract_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockIssuedDuringPeriodValueShareBasedCompensationGross" xlink:label="StockIssuedDuringPeriodValueShareBasedCompensationGross" xlink:title="StockIssuedDuringPeriodValueShareBasedCompensationGross" />
    <link:label xlink:type="resource" xlink:label="us-gaap_StockIssuedDuringPeriodValueShareBasedCompensationGross_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_StockIssuedDuringPeriodValueShareBasedCompensationGross_lbl" xml:lang="en-US" id="us-gaap_StockIssuedDuringPeriodValueShareBasedCompensationGross_lbl">Issuance of common stock in connection with employee stock plans</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockIssuedDuringPeriodValueShareBasedCompensationGross" xlink:to="us-gaap_StockIssuedDuringPeriodValueShareBasedCompensationGross_lbl" xlink:title="label: StockIssuedDuringPeriodValueShareBasedCompensationGross to us-gaap_StockIssuedDuringPeriodValueShareBasedCompensationGross_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_StockIssuedDuringPeriodValueShareBasedCompensationGross_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_StockIssuedDuringPeriodValueShareBasedCompensationGross_lbl1" xml:lang="en-US" id="us-gaap_StockIssuedDuringPeriodValueShareBasedCompensationGross_lbl1">Shares Issued, Value, Share-Based Payment Arrangement, before Forfeiture</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockIssuedDuringPeriodValueShareBasedCompensationGross" xlink:to="us-gaap_StockIssuedDuringPeriodValueShareBasedCompensationGross_lbl1" xlink:title="label: StockIssuedDuringPeriodValueShareBasedCompensationGross to us-gaap_StockIssuedDuringPeriodValueShareBasedCompensationGross_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation" xlink:label="StockIssuedDuringPeriodSharesShareBasedCompensation" xlink:title="StockIssuedDuringPeriodSharesShareBasedCompensation" />
    <link:label xlink:type="resource" xlink:label="us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation_lbl" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation_lbl" xml:lang="en-US" id="us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation_lbl">Issuance of common stock in connection with employee stock plans (in shares)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockIssuedDuringPeriodSharesShareBasedCompensation" xlink:to="us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation_lbl" xlink:title="label: StockIssuedDuringPeriodSharesShareBasedCompensation to us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation_lbl1" xml:lang="en-US" id="us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation_lbl1">Shares Issued, Shares, Share-Based Payment Arrangement, after Forfeiture</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockIssuedDuringPeriodSharesShareBasedCompensation" xlink:to="us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation_lbl1" xlink:title="label: StockIssuedDuringPeriodSharesShareBasedCompensation to us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockholdersEquity" xlink:label="StockholdersEquity" xlink:title="StockholdersEquity" />
    <link:label xlink:type="resource" xlink:label="us-gaap_StockholdersEquity_lbl" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_StockholdersEquity_lbl" xml:lang="en-US" id="us-gaap_StockholdersEquity_lbl">Total stockholders' equity</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockholdersEquity" xlink:to="us-gaap_StockholdersEquity_lbl" xlink:title="label: StockholdersEquity to us-gaap_StockholdersEquity_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_StockholdersEquity_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_StockholdersEquity_lbl1" xml:lang="en-US" id="us-gaap_StockholdersEquity_lbl1">Stockholders' Equity Attributable to Parent</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockholdersEquity" xlink:to="us-gaap_StockholdersEquity_lbl1" xlink:title="label: StockholdersEquity to us-gaap_StockholdersEquity_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" xlink:label="StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" xlink:title="StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" />
    <link:label xlink:type="resource" xlink:label="us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest_lbl" xlink:role="http://www.xbrl.org/2003/role/periodEndLabel" xlink:title="us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest_lbl" xml:lang="en-US" id="us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest_lbl">Balance</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" xlink:to="us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest_lbl" xlink:title="label: StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest to us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest_lbl1" xlink:role="http://www.xbrl.org/2003/role/periodStartLabel" xlink:title="us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest_lbl1" xml:lang="en-US" id="us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest_lbl1">Balance</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" xlink:to="us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest_lbl1" xlink:title="label: StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest to us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest_lbl1" />
    <link:label xlink:type="resource" xlink:label="us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest_lbl2" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest_lbl2" xml:lang="en-US" id="us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest_lbl2">Stockholders' Equity, Including Portion Attributable to Noncontrolling Interest</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest" xlink:to="us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest_lbl2" xlink:title="label: StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest to us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest_lbl2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_StockholdersEquityAbstract" xlink:label="StockholdersEquityAbstract" xlink:title="StockholdersEquityAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_StockholdersEquityAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_StockholdersEquityAbstract_lbl" xml:lang="en-US" id="us-gaap_StockholdersEquityAbstract_lbl">Stockholders' equity:</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockholdersEquityAbstract" xlink:to="us-gaap_StockholdersEquityAbstract_lbl" xlink:title="label: StockholdersEquityAbstract to us-gaap_StockholdersEquityAbstract_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_StockholdersEquityAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_StockholdersEquityAbstract_lbl1" xml:lang="en-US" id="us-gaap_StockholdersEquityAbstract_lbl1">Stockholders' Equity Attributable to Parent [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockholdersEquityAbstract" xlink:to="us-gaap_StockholdersEquityAbstract_lbl1" xlink:title="label: StockholdersEquityAbstract to us-gaap_StockholdersEquityAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SubsequentEventTypeDomain" xlink:label="SubsequentEventTypeDomain" xlink:title="SubsequentEventTypeDomain" />
    <link:label xlink:type="resource" xlink:label="us-gaap_SubsequentEventTypeDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_SubsequentEventTypeDomain_lbl" xml:lang="en-US" id="us-gaap_SubsequentEventTypeDomain_lbl">Subsequent Event Type [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SubsequentEventTypeDomain" xlink:to="us-gaap_SubsequentEventTypeDomain_lbl" xlink:title="label: SubsequentEventTypeDomain to us-gaap_SubsequentEventTypeDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SubsequentEventMember" xlink:label="SubsequentEventMember" xlink:title="SubsequentEventMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_SubsequentEventMember_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_SubsequentEventMember_lbl" xml:lang="en-US" id="us-gaap_SubsequentEventMember_lbl">Subsequent Event [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SubsequentEventMember" xlink:to="us-gaap_SubsequentEventMember_lbl" xlink:title="label: SubsequentEventMember to us-gaap_SubsequentEventMember_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SubsequentEventTypeAxis" xlink:label="SubsequentEventTypeAxis" xlink:title="SubsequentEventTypeAxis" />
    <link:label xlink:type="resource" xlink:label="us-gaap_SubsequentEventTypeAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_SubsequentEventTypeAxis_lbl" xml:lang="en-US" id="us-gaap_SubsequentEventTypeAxis_lbl">Subsequent Event Type [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SubsequentEventTypeAxis" xlink:to="us-gaap_SubsequentEventTypeAxis_lbl" xlink:title="label: SubsequentEventTypeAxis to us-gaap_SubsequentEventTypeAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SupplementalCashFlowInformationAbstract" xlink:label="SupplementalCashFlowInformationAbstract" xlink:title="SupplementalCashFlowInformationAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_SupplementalCashFlowInformationAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_SupplementalCashFlowInformationAbstract_lbl" xml:lang="en-US" id="us-gaap_SupplementalCashFlowInformationAbstract_lbl">Supplemental disclosures of cash flow information:</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SupplementalCashFlowInformationAbstract" xlink:to="us-gaap_SupplementalCashFlowInformationAbstract_lbl" xlink:title="label: SupplementalCashFlowInformationAbstract to us-gaap_SupplementalCashFlowInformationAbstract_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_SupplementalCashFlowInformationAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_SupplementalCashFlowInformationAbstract_lbl1" xml:lang="en-US" id="us-gaap_SupplementalCashFlowInformationAbstract_lbl1">Supplemental Cash Flow Information [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SupplementalCashFlowInformationAbstract" xlink:to="us-gaap_SupplementalCashFlowInformationAbstract_lbl1" xlink:title="label: SupplementalCashFlowInformationAbstract to us-gaap_SupplementalCashFlowInformationAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_SupplementalBalanceSheetDisclosuresTextBlock" xlink:label="SupplementalBalanceSheetDisclosuresTextBlock" xlink:title="SupplementalBalanceSheetDisclosuresTextBlock" />
    <link:label xlink:type="resource" xlink:label="us-gaap_SupplementalBalanceSheetDisclosuresTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_SupplementalBalanceSheetDisclosuresTextBlock_lbl" xml:lang="en-US" id="us-gaap_SupplementalBalanceSheetDisclosuresTextBlock_lbl">Supplemental Financial Data [Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SupplementalBalanceSheetDisclosuresTextBlock" xlink:to="us-gaap_SupplementalBalanceSheetDisclosuresTextBlock_lbl" xlink:title="label: SupplementalBalanceSheetDisclosuresTextBlock to us-gaap_SupplementalBalanceSheetDisclosuresTextBlock_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2022/elts/us-gaap-2022.xsd#us-gaap_TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain" xlink:label="TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain" xlink:title="TransfersAndServicingOfFinancialInstrumentsTypesOfFinancialInstrumentsDomain" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_VestingAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_VestingAxis_lbl" xml:lang="en-US" id="us-gaap_VestingAxis_lbl">Vesting [Axis]</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/label" xlink:title="us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding_lbl" xml:lang="en-US" id="us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding_lbl">Shares used in computing diluted net loss per share (in shares)</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2022/elts/srt-2022.xsd#srt_ExecutiveOfficerMember" xlink:label="ExecutiveOfficerMember" xlink:title="ExecutiveOfficerMember" />
    <link:label xlink:type="resource" xlink:label="srt_ExecutiveOfficerMember_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_ExecutiveOfficerMember_lbl" xml:lang="en-US" id="srt_ExecutiveOfficerMember_lbl">Section 16 Officers [Member]</link:label>
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    <link:label xlink:type="resource" xlink:label="srt_MinimumMember_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_MinimumMember_lbl" xml:lang="en-US" id="srt_MinimumMember_lbl">Minimum [Member]</link:label>
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    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.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/2022/dei-2022.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/2022/dei-2022.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/2022/dei-2022.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/2022/dei-2022.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/2022/dei-2022.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/2022/dei-2022.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/2022/dei-2022.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/2022/dei-2022.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/2022/dei-2022.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/2022/dei-2022.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/2022/dei-2022.xsd#dei_EntityAddressAddressLine2" xlink:label="EntityAddressAddressLine2" xlink:title="EntityAddressAddressLine2" />
    <link:label xlink:type="resource" xlink:label="dei_EntityAddressAddressLine2_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityAddressAddressLine2_lbl" xml:lang="en-US" id="dei_EntityAddressAddressLine2_lbl">Entity Address, Address Line Two</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityAddressAddressLine2" xlink:to="dei_EntityAddressAddressLine2_lbl" xlink:title="label: EntityAddressAddressLine2 to dei_EntityAddressAddressLine2_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityAddressAddressLine3" xlink:label="EntityAddressAddressLine3" xlink:title="EntityAddressAddressLine3" />
    <link:label xlink:type="resource" xlink:label="dei_EntityAddressAddressLine3_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityAddressAddressLine3_lbl" xml:lang="en-US" id="dei_EntityAddressAddressLine3_lbl">Entity Address, Address Line Three</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityAddressAddressLine3" xlink:to="dei_EntityAddressAddressLine3_lbl" xlink:title="label: EntityAddressAddressLine3 to dei_EntityAddressAddressLine3_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.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/2022/dei-2022.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/2022/dei-2022.xsd#dei_EntityAddressCountry" xlink:label="EntityAddressCountry" xlink:title="EntityAddressCountry" />
    <link:label xlink:type="resource" xlink:label="dei_EntityAddressCountry_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_EntityAddressCountry_lbl" xml:lang="en-US" id="dei_EntityAddressCountry_lbl">Entity Address, Country</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EntityAddressCountry" xlink:to="dei_EntityAddressCountry_lbl" xlink:title="label: EntityAddressCountry to dei_EntityAddressCountry_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.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/2022/dei-2022.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/2022/dei-2022.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/2022/dei-2022.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/2022/dei-2022.xsd#dei_NoTradingSymbolFlag" xlink:label="NoTradingSymbolFlag" xlink:title="NoTradingSymbolFlag" />
    <link:label xlink:type="resource" xlink:label="dei_NoTradingSymbolFlag_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="dei_NoTradingSymbolFlag_lbl" xml:lang="en-US" id="dei_NoTradingSymbolFlag_lbl">No Trading Symbol Flag</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NoTradingSymbolFlag" xlink:to="dei_NoTradingSymbolFlag_lbl" xlink:title="label: NoTradingSymbolFlag to dei_NoTradingSymbolFlag_lbl" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.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/2022/dei-2022.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/2022/dei-2022.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="ions-20230331.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>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss" xlink:to="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss_lbl1" xlink:title="label: DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss to ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss_lbl2" xlink:role="http://www.xbrl.org/2009/role/negatedTotalLabel" 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-20230331.xsd#ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedGain" xlink:label="DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedGain" xlink:title="DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedGain" />
    <link:label xlink:type="resource" xlink:label="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedGain_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedGain_lbl" xml:lang="en-US" id="ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedGain_lbl">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).</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_ProceedsFromSaleOfFutureRoyalties_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ProceedsFromSaleOfFutureRoyalties_lbl1" xml:lang="en-US" id="ions_ProceedsFromSaleOfFutureRoyalties_lbl1">Proceeds from Sale of Future Royalties</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ProceedsFromSaleOfFutureRoyalties" xlink:to="ions_ProceedsFromSaleOfFutureRoyalties_lbl1" xlink:title="label: ProceedsFromSaleOfFutureRoyalties to ions_ProceedsFromSaleOfFutureRoyalties_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ProceedsFromSaleOfFutureRoyalties_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ProceedsFromSaleOfFutureRoyalties_lbl2" xml:lang="en-US" id="ions_ProceedsFromSaleOfFutureRoyalties_lbl2">Proceeds from sale of future royalties</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ProceedsFromSaleOfFutureRoyalties" xlink:to="ions_ProceedsFromSaleOfFutureRoyalties_lbl2" xlink:title="label: ProceedsFromSaleOfFutureRoyalties to ions_ProceedsFromSaleOfFutureRoyalties_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.xsd#ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties" xlink:label="PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties" xlink:title="PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties_lbl" xml:lang="en-US" id="ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties_lbl">The cash outflow paid to third parties for transaction costs in connection with a monetization transaction of future SPINRAZA and pelacarsen royalties the Company is entitled to under collaboration and licensing agreements.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties_lbl1" xml:lang="en-US" id="ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties_lbl1">Payments for Transaction Costs Related to Sale of Future Royalties</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties" xlink:to="ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties_lbl1" xlink:title="label: PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties to ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties_lbl2" xml:lang="en-US" id="ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties_lbl2">Transaction costs</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties" xlink:to="ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties_lbl2" xlink:title="label: PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties to ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties_lbl2" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties_lbl3" xlink:role="http://www.xbrl.org/2009/role/negatedTerseLabel" xlink:title="ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties_lbl3" xml:lang="en-US" id="ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties_lbl3">Payments of transaction costs related to sale of future royalties</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties" xlink:to="ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties_lbl3" xlink:title="label: PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties to ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties_lbl3" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.xsd#ions_InterestExpenseRelatedToSaleOfFutureRoyalties" xlink:label="InterestExpenseRelatedToSaleOfFutureRoyalties" xlink:title="InterestExpenseRelatedToSaleOfFutureRoyalties" />
    <link:label xlink:type="resource" xlink:label="ions_InterestExpenseRelatedToSaleOfFutureRoyalties_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_InterestExpenseRelatedToSaleOfFutureRoyalties_lbl" xml:lang="en-US" id="ions_InterestExpenseRelatedToSaleOfFutureRoyalties_lbl">Amount of interest expense using the effective interest rate method related to the sale of future royalties.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InterestExpenseRelatedToSaleOfFutureRoyalties" xlink:to="ions_InterestExpenseRelatedToSaleOfFutureRoyalties_lbl" xlink:title="label: InterestExpenseRelatedToSaleOfFutureRoyalties to ions_InterestExpenseRelatedToSaleOfFutureRoyalties_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_InterestExpenseRelatedToSaleOfFutureRoyalties_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_InterestExpenseRelatedToSaleOfFutureRoyalties_lbl1" xml:lang="en-US" id="ions_InterestExpenseRelatedToSaleOfFutureRoyalties_lbl1">Interest Expense Related to Sale of Future Royalties</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InterestExpenseRelatedToSaleOfFutureRoyalties" xlink:to="ions_InterestExpenseRelatedToSaleOfFutureRoyalties_lbl1" xlink:title="label: InterestExpenseRelatedToSaleOfFutureRoyalties to ions_InterestExpenseRelatedToSaleOfFutureRoyalties_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_InterestExpenseRelatedToSaleOfFutureRoyalties_lbl2" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_InterestExpenseRelatedToSaleOfFutureRoyalties_lbl2" xml:lang="en-US" id="ions_InterestExpenseRelatedToSaleOfFutureRoyalties_lbl2">Non-cash interest related to sale of future royalties</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InterestExpenseRelatedToSaleOfFutureRoyalties" xlink:to="ions_InterestExpenseRelatedToSaleOfFutureRoyalties_lbl2" xlink:title="label: InterestExpenseRelatedToSaleOfFutureRoyalties to ions_InterestExpenseRelatedToSaleOfFutureRoyalties_lbl2" />
    <link:label xlink:type="resource" xlink:label="ions_InterestExpenseRelatedToSaleOfFutureRoyalties_lbl3" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_InterestExpenseRelatedToSaleOfFutureRoyalties_lbl3" xml:lang="en-US" id="ions_InterestExpenseRelatedToSaleOfFutureRoyalties_lbl3">Interest expense related to sale of future royalties</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InterestExpenseRelatedToSaleOfFutureRoyalties" xlink:to="ions_InterestExpenseRelatedToSaleOfFutureRoyalties_lbl3" xlink:title="label: InterestExpenseRelatedToSaleOfFutureRoyalties to ions_InterestExpenseRelatedToSaleOfFutureRoyalties_lbl3" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.xsd#ions_NonCashCapitalAndPatentExpenditures" xlink:label="NonCashCapitalAndPatentExpenditures" xlink:title="NonCashCapitalAndPatentExpenditures" />
    <link:label xlink:type="resource" xlink:label="ions_NonCashCapitalAndPatentExpenditures_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NonCashCapitalAndPatentExpenditures_lbl" xml:lang="en-US" id="ions_NonCashCapitalAndPatentExpenditures_lbl">Future cash outflow to pay for purchases of fixed assets and patents that have been incurred.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NonCashCapitalAndPatentExpenditures" xlink:to="ions_NonCashCapitalAndPatentExpenditures_lbl" xlink:title="label: NonCashCapitalAndPatentExpenditures to ions_NonCashCapitalAndPatentExpenditures_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NonCashCapitalAndPatentExpenditures_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NonCashCapitalAndPatentExpenditures_lbl1" xml:lang="en-US" id="ions_NonCashCapitalAndPatentExpenditures_lbl1">Non-cash Capital and Patent Expenditures</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NonCashCapitalAndPatentExpenditures" xlink:to="ions_NonCashCapitalAndPatentExpenditures_lbl1" xlink:title="label: NonCashCapitalAndPatentExpenditures to ions_NonCashCapitalAndPatentExpenditures_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NonCashCapitalAndPatentExpenditures_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NonCashCapitalAndPatentExpenditures_lbl2" xml:lang="en-US" id="ions_NonCashCapitalAndPatentExpenditures_lbl2">Amounts accrued for capital and patent expenditures</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NonCashCapitalAndPatentExpenditures" xlink:to="ions_NonCashCapitalAndPatentExpenditures_lbl2" xlink:title="label: NonCashCapitalAndPatentExpenditures to ions_NonCashCapitalAndPatentExpenditures_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.xsd#ions_InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties" xlink:label="InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties" xlink:title="InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties" />
    <link:label xlink:type="resource" xlink:label="ions_InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties_lbl" xml:lang="en-US" id="ions_InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties_lbl">Amount of interest expense using the effective interest rate method and amortization of issuance costs related to the sale of future royalties.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties" xlink:to="ions_InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties_lbl" xlink:title="label: InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties to ions_InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties_lbl1" xml:lang="en-US" id="ions_InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties_lbl1">Interest Expense and Amortization of Issuance Costs Related to Sale of Future Royalties</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties" xlink:to="ions_InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties_lbl1" xlink:title="label: InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties to ions_InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties_lbl2" xlink:role="http://www.xbrl.org/2009/role/negatedLabel" xlink:title="ions_InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties_lbl2" xml:lang="en-US" id="ions_InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties_lbl2">Interest expense related to sale of future royalties</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties" xlink:to="ions_InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties_lbl2" xlink:title="label: InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties to ions_InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.xsd#ions_CollaborativeAgreementRevenueMember" xlink:label="CollaborativeAgreementRevenueMember" xlink:title="CollaborativeAgreementRevenueMember" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeAgreementRevenueMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CollaborativeAgreementRevenueMember_lbl" xml:lang="en-US" id="ions_CollaborativeAgreementRevenueMember_lbl">Revenue from research and development services performed under a collaborative agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeAgreementRevenueMember" xlink:to="ions_CollaborativeAgreementRevenueMember_lbl" xlink:title="label: CollaborativeAgreementRevenueMember to ions_CollaborativeAgreementRevenueMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeAgreementRevenueMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CollaborativeAgreementRevenueMember_lbl1" xml:lang="en-US" id="ions_CollaborativeAgreementRevenueMember_lbl1">Collaborative Agreement Revenue [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeAgreementRevenueMember" xlink:to="ions_CollaborativeAgreementRevenueMember_lbl1" xlink:title="label: CollaborativeAgreementRevenueMember to ions_CollaborativeAgreementRevenueMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeAgreementRevenueMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CollaborativeAgreementRevenueMember_lbl2" xml:lang="en-US" id="ions_CollaborativeAgreementRevenueMember_lbl2">Collaborative Agreement Revenue [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeAgreementRevenueMember" xlink:to="ions_CollaborativeAgreementRevenueMember_lbl2" xlink:title="label: CollaborativeAgreementRevenueMember to ions_CollaborativeAgreementRevenueMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.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/verboseLabel" xlink:title="ions_LicensingAndOtherRoyaltiesMember_lbl2" xml:lang="en-US" id="ions_LicensingAndOtherRoyaltiesMember_lbl2">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_lbl2" xlink:title="label: LicensingAndOtherRoyaltiesMember to ions_LicensingAndOtherRoyaltiesMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.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-20230331.xsd#ions_CommercialMember" xlink:label="CommercialMember" xlink:title="CommercialMember" />
    <link:label xlink:type="resource" xlink:label="ions_CommercialMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CommercialMember_lbl" xml:lang="en-US" id="ions_CommercialMember_lbl">Revenue from the sale of medicines commercially as well as licensing and royalty revenues from other medicines, including SPINRAZA..</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CommercialMember" xlink:to="ions_CommercialMember_lbl" xlink:title="label: CommercialMember to ions_CommercialMember_lbl" />
    <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-20230331.xsd#ions_EplontersenJointDevelopmentRevenueMember" xlink:label="EplontersenJointDevelopmentRevenueMember" xlink:title="EplontersenJointDevelopmentRevenueMember" />
    <link:label xlink:type="resource" xlink:label="ions_EplontersenJointDevelopmentRevenueMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_EplontersenJointDevelopmentRevenueMember_lbl" xml:lang="en-US" id="ions_EplontersenJointDevelopmentRevenueMember_lbl">Joint development revenue for eplontersen.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EplontersenJointDevelopmentRevenueMember" xlink:to="ions_EplontersenJointDevelopmentRevenueMember_lbl" xlink:title="label: EplontersenJointDevelopmentRevenueMember to ions_EplontersenJointDevelopmentRevenueMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_EplontersenJointDevelopmentRevenueMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_EplontersenJointDevelopmentRevenueMember_lbl1" xml:lang="en-US" id="ions_EplontersenJointDevelopmentRevenueMember_lbl1">Eplontersen Joint Development Revenue [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EplontersenJointDevelopmentRevenueMember" xlink:to="ions_EplontersenJointDevelopmentRevenueMember_lbl1" xlink:title="label: EplontersenJointDevelopmentRevenueMember to ions_EplontersenJointDevelopmentRevenueMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_EplontersenJointDevelopmentRevenueMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_EplontersenJointDevelopmentRevenueMember_lbl2" xml:lang="en-US" id="ions_EplontersenJointDevelopmentRevenueMember_lbl2">Eplontersen Joint Development Revenue [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EplontersenJointDevelopmentRevenueMember" xlink:to="ions_EplontersenJointDevelopmentRevenueMember_lbl2" xlink:title="label: EplontersenJointDevelopmentRevenueMember to ions_EplontersenJointDevelopmentRevenueMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.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-20230331.xsd#ions_ResearchAndDevelopmentRevenueMember" xlink:label="ResearchAndDevelopmentRevenueMember" xlink:title="ResearchAndDevelopmentRevenueMember" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentRevenueMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ResearchAndDevelopmentRevenueMember_lbl" xml:lang="en-US" id="ions_ResearchAndDevelopmentRevenueMember_lbl">Revenue from research and development services.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentRevenueMember" xlink:to="ions_ResearchAndDevelopmentRevenueMember_lbl" xlink:title="label: ResearchAndDevelopmentRevenueMember to ions_ResearchAndDevelopmentRevenueMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentRevenueMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ResearchAndDevelopmentRevenueMember_lbl1" xml:lang="en-US" id="ions_ResearchAndDevelopmentRevenueMember_lbl1">Research and Development Revenue [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentRevenueMember" xlink:to="ions_ResearchAndDevelopmentRevenueMember_lbl1" xlink:title="label: ResearchAndDevelopmentRevenueMember to ions_ResearchAndDevelopmentRevenueMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentRevenueMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_ResearchAndDevelopmentRevenueMember_lbl2" xml:lang="en-US" id="ions_ResearchAndDevelopmentRevenueMember_lbl2">Research and Development Revenue [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentRevenueMember" xlink:to="ions_ResearchAndDevelopmentRevenueMember_lbl2" xlink:title="label: ResearchAndDevelopmentRevenueMember to ions_ResearchAndDevelopmentRevenueMember_lbl2" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentRevenueMember_lbl3" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ResearchAndDevelopmentRevenueMember_lbl3" xml:lang="en-US" id="ions_ResearchAndDevelopmentRevenueMember_lbl3">R&amp;D Revenue [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentRevenueMember" xlink:to="ions_ResearchAndDevelopmentRevenueMember_lbl3" xlink:title="label: ResearchAndDevelopmentRevenueMember to ions_ResearchAndDevelopmentRevenueMember_lbl3" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.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>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumContractMaturityPeriodRange3" xlink:to="ions_MaximumContractMaturityPeriodRange3_lbl" xlink:title="label: MaximumContractMaturityPeriodRange3 to ions_MaximumContractMaturityPeriodRange3_lbl" />
    <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>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumContractMaturityPeriodRange3" xlink:to="ions_MaximumContractMaturityPeriodRange3_lbl1" xlink:title="label: MaximumContractMaturityPeriodRange3 to ions_MaximumContractMaturityPeriodRange3_lbl1" />
    <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>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumContractMaturityPeriodRange3" xlink:to="ions_MaximumContractMaturityPeriodRange3_lbl2" xlink:title="label: MaximumContractMaturityPeriodRange3 to ions_MaximumContractMaturityPeriodRange3_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.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>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumContractMaturityPeriodRange2" xlink:to="ions_MaximumContractMaturityPeriodRange2_lbl" xlink:title="label: MaximumContractMaturityPeriodRange2 to ions_MaximumContractMaturityPeriodRange2_lbl" />
    <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-20230331.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>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumContractMaturityPeriodRange1" xlink:to="ions_MaximumContractMaturityPeriodRange1_lbl" xlink:title="label: MaximumContractMaturityPeriodRange1 to ions_MaximumContractMaturityPeriodRange1_lbl" />
    <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>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumContractMaturityPeriodRange1" xlink:to="ions_MaximumContractMaturityPeriodRange1_lbl1" xlink:title="label: MaximumContractMaturityPeriodRange1 to ions_MaximumContractMaturityPeriodRange1_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumContractMaturityPeriodRange1_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumContractMaturityPeriodRange1_lbl2" xml:lang="en-US" id="ions_MaximumContractMaturityPeriodRange1_lbl2">Maximum contract maturity period, range 1</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumContractMaturityPeriodRange1" xlink:to="ions_MaximumContractMaturityPeriodRange1_lbl2" xlink:title="label: MaximumContractMaturityPeriodRange1 to ions_MaximumContractMaturityPeriodRange1_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.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>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage" xlink:to="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage_lbl" xlink:title="label: AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage to ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage_lbl" />
    <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>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage" xlink:to="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage_lbl1" xlink:title="label: AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage to ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage_lbl1" />
    <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>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage" xlink:to="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage_lbl2" xlink:title="label: AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage to ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.xsd#ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage" xlink:label="AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage" xlink:title="AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage" />
    <link:label xlink:type="resource" xlink:label="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage_lbl" xml:lang="en-US" id="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage_lbl">The percentage of available-for-sale debt securities that mature beyond one year but within two years of the balance sheet date.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage" xlink:to="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage_lbl" xlink:title="label: AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage to ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage_lbl1" xml:lang="en-US" id="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage_lbl1">Available-for-sale Securities, Debt Maturities, after One Through Two Years, Percentage</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage" xlink:to="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage_lbl1" xlink:title="label: AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage to ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage_lbl2" xml:lang="en-US" id="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage_lbl2">After one year but within two years</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage" xlink:to="ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage_lbl2" xlink:title="label: AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage to ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.xsd#ions_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage" xlink:label="AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage" xlink:title="AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage" />
    <link:label xlink:type="resource" xlink:label="ions_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage_lbl" xml:lang="en-US" id="ions_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage_lbl">The aggregate percentage of all available-for-sale debt securities, regardless of maturity.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage" xlink:to="ions_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage_lbl" xlink:title="label: AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage to ions_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage_lbl1" xml:lang="en-US" id="ions_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage_lbl1">Available-for-sale Securities, Debt Maturities, Total, Percentage</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage" xlink:to="ions_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage_lbl1" xlink:title="label: AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage to ions_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage_lbl2" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="ions_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage_lbl2" xml:lang="en-US" id="ions_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage_lbl2">Total</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage" xlink:to="ions_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage_lbl2" xlink:title="label: AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage to ions_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.xsd#ions_AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage" xlink:label="AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage" xlink:title="AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage" />
    <link:label xlink:type="resource" xlink:label="ions_AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage_lbl" xml:lang="en-US" id="ions_AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage_lbl">The percentage of available-for-sale debt securities that mature within two years of the balance sheet date.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage" xlink:to="ions_AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage_lbl" xlink:title="label: AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage to ions_AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage_lbl1" xml:lang="en-US" id="ions_AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage_lbl1">Available-for-sale Securities, Debt Maturities, within Two Years, Percentage</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent_lbl2" xlink:role="http://www.xbrl.org/2009/role/negatedLabel" xlink:title="ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent_lbl2" xml:lang="en-US" id="ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent_lbl2">Gross unrealized losses</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent" xlink:to="ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent_lbl2" xlink:title="label: DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent to ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.xsd#ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent" xlink:label="DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent" xlink:title="DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent" />
    <link:label xlink:type="resource" xlink:label="ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent_lbl" xml:lang="en-US" id="ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent_lbl">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), classified as noncurrent.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent" xlink:to="ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent_lbl" xlink:title="label: DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent to ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent_lbl1" xml:lang="en-US" id="ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent_lbl1">Debt Securities, Available-for-sale, Accumulated Gross Unrealized Gain, before Tax, Noncurrent</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent" xlink:to="ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent_lbl1" xlink:title="label: DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent to ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent_lbl2" xml:lang="en-US" id="ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent_lbl2">Gross unrealized gains</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent" xlink:to="ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent_lbl2" xlink:title="label: DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent to ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.xsd#ions_BepirovirsenMember" xlink:label="BepirovirsenMember" xlink:title="BepirovirsenMember" />
    <link:label xlink:type="resource" xlink:label="ions_BepirovirsenMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_BepirovirsenMember_lbl" xml:lang="en-US" id="ions_BepirovirsenMember_lbl">Bepirovirsen is a potential first-in-class treatment for chronic hepatitis B infection (CHB), uniquely designed to simultaneously reduce hepatitis B virus (HBV) replication and suppress viral antigens in hopes of stimulating innate immunity to help attain functional cure for patients.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BepirovirsenMember" xlink:to="ions_BepirovirsenMember_lbl" xlink:title="label: BepirovirsenMember to ions_BepirovirsenMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_BepirovirsenMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_BepirovirsenMember_lbl1" xml:lang="en-US" id="ions_BepirovirsenMember_lbl1">Bepirovirsen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BepirovirsenMember" xlink:to="ions_BepirovirsenMember_lbl1" xlink:title="label: BepirovirsenMember to ions_BepirovirsenMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_BepirovirsenMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_BepirovirsenMember_lbl2" xml:lang="en-US" id="ions_BepirovirsenMember_lbl2">Bepirovirsen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BepirovirsenMember" xlink:to="ions_BepirovirsenMember_lbl2" xlink:title="label: BepirovirsenMember to ions_BepirovirsenMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.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-20230331.xsd#ions_NextPaymentToBeAchieved" xlink:label="NextPaymentToBeAchieved" xlink:title="NextPaymentToBeAchieved" />
    <link:label xlink:type="resource" xlink:label="ions_NextPaymentToBeAchieved_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NextPaymentToBeAchieved_lbl" xml:lang="en-US" id="ions_NextPaymentToBeAchieved_lbl">The next payment to be achieved under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NextPaymentToBeAchieved" xlink:to="ions_NextPaymentToBeAchieved_lbl" xlink:title="label: NextPaymentToBeAchieved to ions_NextPaymentToBeAchieved_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NextPaymentToBeAchieved_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NextPaymentToBeAchieved_lbl1" xml:lang="en-US" id="ions_NextPaymentToBeAchieved_lbl1">Next payment to be achieved</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NextPaymentToBeAchieved" xlink:to="ions_NextPaymentToBeAchieved_lbl1" xlink:title="label: NextPaymentToBeAchieved to ions_NextPaymentToBeAchieved_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NextPaymentToBeAchieved_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NextPaymentToBeAchieved_lbl2" xml:lang="en-US" id="ions_NextPaymentToBeAchieved_lbl2">Next payment to be achieved</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NextPaymentToBeAchieved" xlink:to="ions_NextPaymentToBeAchieved_lbl2" xlink:title="label: NextPaymentToBeAchieved to ions_NextPaymentToBeAchieved_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.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-20230331.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-20230331.xsd#ions_TofersenMember" xlink:label="TofersenMember" xlink:title="TofersenMember" />
    <link:label xlink:type="resource" xlink:label="ions_TofersenMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_TofersenMember_lbl" xml:lang="en-US" id="ions_TofersenMember_lbl">Tofersen (IONIS-SOD1Rx or BIIB067), or QALSODY, is an antisense medicine designed to inhibit the production of superoxide dismutase 1, or SOD1, which is a well understood genetic cause of familial amyotrophic lateral sclerosis, or ALS.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="TofersenMember" xlink:to="ions_TofersenMember_lbl" xlink:title="label: TofersenMember to ions_TofersenMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_TofersenMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_TofersenMember_lbl1" xml:lang="en-US" id="ions_TofersenMember_lbl1">Tofersen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="TofersenMember" xlink:to="ions_TofersenMember_lbl1" xlink:title="label: TofersenMember to ions_TofersenMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_TofersenMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_TofersenMember_lbl2" xml:lang="en-US" id="ions_TofersenMember_lbl2">Tofersen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="TofersenMember" xlink:to="ions_TofersenMember_lbl2" xlink:title="label: TofersenMember to ions_TofersenMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.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-20230331.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-20230331.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/verboseLabel" xlink:title="ions_BiogenCollaborationsMember_lbl2" xml:lang="en-US" id="ions_BiogenCollaborationsMember_lbl2">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_lbl2" xlink:title="label: BiogenCollaborationsMember to ions_BiogenCollaborationsMember_lbl2" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenCollaborationsMember_lbl3" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_BiogenCollaborationsMember_lbl3" xml:lang="en-US" id="ions_BiogenCollaborationsMember_lbl3">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_lbl3" xlink:title="label: BiogenCollaborationsMember to ions_BiogenCollaborationsMember_lbl3" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.xsd#ions_MilestonePaymentEarnedAndRecognizedAsRevenueAsServicesArePerformed" xlink:label="MilestonePaymentEarnedAndRecognizedAsRevenueAsServicesArePerformed" xlink:title="MilestonePaymentEarnedAndRecognizedAsRevenueAsServicesArePerformed" />
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    <link:loc xlink:type="locator" xlink:href="ions-20230331.xsd#ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureTable" xlink:label="CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureTable" xlink:title="CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureTable" />
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    <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>
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    <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>
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    <link:loc xlink:type="locator" xlink:href="ions-20230331.xsd#ions_ConvertibleNotesDisclosureTable" xlink:label="ConvertibleNotesDisclosureTable" xlink:title="ConvertibleNotesDisclosureTable" />
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    <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-20230331.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>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleNotesDisclosureLineItems" xlink:to="ions_ConvertibleNotesDisclosureLineItems_lbl" xlink:title="label: ConvertibleNotesDisclosureLineItems to ions_ConvertibleNotesDisclosureLineItems_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleNotesDisclosureLineItems_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ConvertibleNotesDisclosureLineItems_lbl1" xml:lang="en-US" id="ions_ConvertibleNotesDisclosureLineItems_lbl1">Convertible Notes Disclosure [Line Items]</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20230331.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>
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    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes1PercentMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_ConvertibleSeniorNotes1PercentMember_lbl2" xml:lang="en-US" id="ions_ConvertibleSeniorNotes1PercentMember_lbl2">1% Notes [Member]</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20230331.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>
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    <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-20230331.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>
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    <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>
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    <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-20230331.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>
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    <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>
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    <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>
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    <link:loc xlink:type="locator" xlink:href="ions-20230331.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>
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    <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-20230331.xsd#ions_LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock" xlink:label="LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock" xlink:title="LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock" />
    <link:label xlink:type="resource" xlink:label="ions_LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock_lbl" xml:lang="en-US" id="ions_LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock_lbl">Disclosure of inventory accounting policy for liability related to sale of future royalties.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock" xlink:to="ions_LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock_lbl" xlink:title="label: LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock to ions_LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock_lbl1" xml:lang="en-US" id="ions_LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock_lbl1">Liability Related to Sale of Future Royalties, Policy [Policy Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock" xlink:to="ions_LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock_lbl1" xlink:title="label: LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock to ions_LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock_lbl2" xml:lang="en-US" id="ions_LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock_lbl2">Liability Related to Sale of Future Royalties</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock" xlink:to="ions_LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock_lbl2" xlink:title="label: LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock to ions_LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.xsd#ions_SupplementalFinancialDataAbstract" xlink:label="SupplementalFinancialDataAbstract" xlink:title="SupplementalFinancialDataAbstract" />
    <link:label xlink:type="resource" xlink:label="ions_SupplementalFinancialDataAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_SupplementalFinancialDataAbstract_lbl1" xml:lang="en-US" id="ions_SupplementalFinancialDataAbstract_lbl1">Supplemental Financial Data [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SupplementalFinancialDataAbstract" xlink:to="ions_SupplementalFinancialDataAbstract_lbl1" xlink:title="label: SupplementalFinancialDataAbstract to ions_SupplementalFinancialDataAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.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-20230331.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-20230331.xsd#ions_AccruedClinicalDevelopmentExpenses" xlink:label="AccruedClinicalDevelopmentExpenses" xlink:title="AccruedClinicalDevelopmentExpenses" />
    <link:label xlink:type="resource" xlink:label="ions_AccruedClinicalDevelopmentExpenses_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AccruedClinicalDevelopmentExpenses_lbl" xml:lang="en-US" id="ions_AccruedClinicalDevelopmentExpenses_lbl">Carrying value as of the balance sheet date of obligations incurred through that date and payable for clinical development 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="AccruedClinicalDevelopmentExpenses" xlink:to="ions_AccruedClinicalDevelopmentExpenses_lbl" xlink:title="label: AccruedClinicalDevelopmentExpenses to ions_AccruedClinicalDevelopmentExpenses_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AccruedClinicalDevelopmentExpenses_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AccruedClinicalDevelopmentExpenses_lbl1" xml:lang="en-US" id="ions_AccruedClinicalDevelopmentExpenses_lbl1">Accrued clinical development expenses</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccruedClinicalDevelopmentExpenses" xlink:to="ions_AccruedClinicalDevelopmentExpenses_lbl1" xlink:title="label: AccruedClinicalDevelopmentExpenses to ions_AccruedClinicalDevelopmentExpenses_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_AccruedClinicalDevelopmentExpenses_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_AccruedClinicalDevelopmentExpenses_lbl2" xml:lang="en-US" id="ions_AccruedClinicalDevelopmentExpenses_lbl2">Clinical development expenses</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AccruedClinicalDevelopmentExpenses" xlink:to="ions_AccruedClinicalDevelopmentExpenses_lbl2" xlink:title="label: AccruedClinicalDevelopmentExpenses to ions_AccruedClinicalDevelopmentExpenses_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.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-20230331.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" />
    <link:label xlink:type="resource" xlink:label="ions_AccruedCommercialExpensesCurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AccruedCommercialExpensesCurrent_lbl1" xml:lang="en-US" id="ions_AccruedCommercialExpensesCurrent_lbl1">Accrued commercial expenses, Current</link:label>
    <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-20230331.xsd#ions_ShareBasedPaymentArrangementBoardOfDirectorMember" xlink:label="ShareBasedPaymentArrangementBoardOfDirectorMember" xlink:title="ShareBasedPaymentArrangementBoardOfDirectorMember" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedPaymentArrangementBoardOfDirectorMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ShareBasedPaymentArrangementBoardOfDirectorMember_lbl" xml:lang="en-US" id="ions_ShareBasedPaymentArrangementBoardOfDirectorMember_lbl">Recipient, of award granted under share-based payment arrangement, over whom grantor exercises or has right to exercise sufficient control to establish employer-employee relationship based on law of pertinent jurisdiction. Includes nonemployee director treated as employee when acting as member of board of directors, if elected by grantor's shareholders or appointed to board position to be filled by shareholder election when existing term expires.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedPaymentArrangementBoardOfDirectorMember" xlink:to="ions_ShareBasedPaymentArrangementBoardOfDirectorMember_lbl" xlink:title="label: ShareBasedPaymentArrangementBoardOfDirectorMember to ions_ShareBasedPaymentArrangementBoardOfDirectorMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedPaymentArrangementBoardOfDirectorMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ShareBasedPaymentArrangementBoardOfDirectorMember_lbl1" xml:lang="en-US" id="ions_ShareBasedPaymentArrangementBoardOfDirectorMember_lbl1">Share-based Payment Arrangement, Board of Director [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_lbl1" xlink:title="label: ShareBasedPaymentArrangementBoardOfDirectorMember to ions_ShareBasedPaymentArrangementBoardOfDirectorMember_lbl1" />
    <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-20230331.xsd#ions_ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member" xlink:label="ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member" xlink:title="ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member_lbl" xml:lang="en-US" id="ions_ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member_lbl">Share-based payment arrangement granting right, subject to vesting and other restrictions, to purchase or sell certain number of shares at predetermined price for specified period of time granted prior to January 1, 2022.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member" xlink:to="ions_ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member_lbl" xlink:title="label: ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member to ions_ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member_lbl1" xml:lang="en-US" id="ions_ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member_lbl1">Share-based Payment Arrangement, Options Granted Prior to January 1, 2022 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member" xlink:to="ions_ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member_lbl1" xlink:title="label: ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member to ions_ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member_lbl2" xml:lang="en-US" id="ions_ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member_lbl2">Stock Options Granted Prior to January 1, 2022 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member" xlink:to="ions_ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member_lbl2" xlink:title="label: ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member to ions_ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.xsd#ions_ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember" xlink:label="ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember" xlink:title="ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember_lbl" xml:lang="en-US" id="ions_ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember_lbl">Share-based payment arrangement granting right, subject to vesting and other restrictions, to purchase or sell certain number of shares at predetermined price for specified period of time granted on January 1, 2022 and thereafter.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember" xlink:to="ions_ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember_lbl" xlink:title="label: ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember to ions_ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember_lbl1" xml:lang="en-US" id="ions_ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember_lbl1">Share-based Payment Arrangement, Options Granted on January 1, 2022 and Thereafter [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember" xlink:to="ions_ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember_lbl1" xlink:title="label: ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember to ions_ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember_lbl2" xml:lang="en-US" id="ions_ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember_lbl2">Stock Options Granted on January 1, 2022 and Thereafter [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember" xlink:to="ions_ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember_lbl2" xlink:title="label: ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember to ions_ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.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" />
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    <link:loc xlink:type="locator" xlink:href="ions-20230331.xsd#ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest" xlink:label="ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest" xlink:title="ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest" />
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    <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" />
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    <link:loc xlink:type="locator" xlink:href="ions-20230331.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" />
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    <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>
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    <link:loc xlink:type="locator" xlink:href="ions-20230331.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>
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    <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>
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    <link:label xlink:type="resource" xlink:label="ions_ResearchDevelopmentAndPatentExpensesMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_ResearchDevelopmentAndPatentExpensesMember_lbl2" xml:lang="en-US" id="ions_ResearchDevelopmentAndPatentExpensesMember_lbl2">Research, Development and Patent Expense [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-20230331.xsd#ions_LiabilityRelatedToSaleOfFutureRoyaltiesGross" xlink:label="LiabilityRelatedToSaleOfFutureRoyaltiesGross" xlink:title="LiabilityRelatedToSaleOfFutureRoyaltiesGross" />
    <link:label xlink:type="resource" xlink:label="ions_LiabilityRelatedToSaleOfFutureRoyaltiesGross_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LiabilityRelatedToSaleOfFutureRoyaltiesGross_lbl" xml:lang="en-US" id="ions_LiabilityRelatedToSaleOfFutureRoyaltiesGross_lbl">Amount, before accumulated amortization, of the liability related to the sale of future royalties, pursuant to a royalty purchase agreement, that the Company is entitled to receive under collaboration agreements with Biogen and Novartis. The balance will be amortized over the estimated life of the arrangement using the effective interest rate method.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LiabilityRelatedToSaleOfFutureRoyaltiesGross" xlink:to="ions_LiabilityRelatedToSaleOfFutureRoyaltiesGross_lbl" xlink:title="label: LiabilityRelatedToSaleOfFutureRoyaltiesGross to ions_LiabilityRelatedToSaleOfFutureRoyaltiesGross_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LiabilityRelatedToSaleOfFutureRoyaltiesGross_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LiabilityRelatedToSaleOfFutureRoyaltiesGross_lbl1" xml:lang="en-US" id="ions_LiabilityRelatedToSaleOfFutureRoyaltiesGross_lbl1">Liability Related to Sale of Future Royalties, Gross</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LiabilityRelatedToSaleOfFutureRoyaltiesGross" xlink:to="ions_LiabilityRelatedToSaleOfFutureRoyaltiesGross_lbl1" xlink:title="label: LiabilityRelatedToSaleOfFutureRoyaltiesGross to ions_LiabilityRelatedToSaleOfFutureRoyaltiesGross_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LiabilityRelatedToSaleOfFutureRoyaltiesGross_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LiabilityRelatedToSaleOfFutureRoyaltiesGross_lbl2" xml:lang="en-US" id="ions_LiabilityRelatedToSaleOfFutureRoyaltiesGross_lbl2">Liability related to sale of future royalties as of</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LiabilityRelatedToSaleOfFutureRoyaltiesGross" xlink:to="ions_LiabilityRelatedToSaleOfFutureRoyaltiesGross_lbl2" xlink:title="label: LiabilityRelatedToSaleOfFutureRoyaltiesGross to ions_LiabilityRelatedToSaleOfFutureRoyaltiesGross_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.xsd#ions_RoyaltyPurchaseAgreementMember" xlink:label="RoyaltyPurchaseAgreementMember" xlink:title="RoyaltyPurchaseAgreementMember" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPurchaseAgreementMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RoyaltyPurchaseAgreementMember_lbl" xml:lang="en-US" id="ions_RoyaltyPurchaseAgreementMember_lbl">In January 2023, the Company entered into a royalty purchase agreement with Royalty Pharma to monetize a portion of future SPINRAZA and pelacarsen royalties the Company is entitled to under arrangements with Biogen and Novartis, respectively.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPurchaseAgreementMember" xlink:to="ions_RoyaltyPurchaseAgreementMember_lbl" xlink:title="label: RoyaltyPurchaseAgreementMember to ions_RoyaltyPurchaseAgreementMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPurchaseAgreementMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RoyaltyPurchaseAgreementMember_lbl1" xml:lang="en-US" id="ions_RoyaltyPurchaseAgreementMember_lbl1">Royalty Purchase Agreement [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPurchaseAgreementMember" xlink:to="ions_RoyaltyPurchaseAgreementMember_lbl1" xlink:title="label: RoyaltyPurchaseAgreementMember to ions_RoyaltyPurchaseAgreementMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPurchaseAgreementMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RoyaltyPurchaseAgreementMember_lbl2" xml:lang="en-US" id="ions_RoyaltyPurchaseAgreementMember_lbl2">Royalty Purchase Agreement [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPurchaseAgreementMember" xlink:to="ions_RoyaltyPurchaseAgreementMember_lbl2" xlink:title="label: RoyaltyPurchaseAgreementMember to ions_RoyaltyPurchaseAgreementMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.xsd#ions_SpinrazaMember" xlink:label="SpinrazaMember" xlink:title="SpinrazaMember" />
    <link:label xlink:type="resource" xlink:label="ions_SpinrazaMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_SpinrazaMember_lbl" xml:lang="en-US" id="ions_SpinrazaMember_lbl">Nusinersen, marketed as Spinraza, is a medicine used in treating spinal muscular atrophy (SMA), a progressive, debilitating and often fatal genetic disease.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SpinrazaMember" xlink:to="ions_SpinrazaMember_lbl" xlink:title="label: SpinrazaMember to ions_SpinrazaMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_SpinrazaMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_SpinrazaMember_lbl1" xml:lang="en-US" id="ions_SpinrazaMember_lbl1">Spinraza [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SpinrazaMember" xlink:to="ions_SpinrazaMember_lbl1" xlink:title="label: SpinrazaMember to ions_SpinrazaMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_SpinrazaMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_SpinrazaMember_lbl2" xml:lang="en-US" id="ions_SpinrazaMember_lbl2">SPINRAZA [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SpinrazaMember" xlink:to="ions_SpinrazaMember_lbl2" xlink:title="label: SpinrazaMember to ions_SpinrazaMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.xsd#ions_PelacarsenMember" xlink:label="PelacarsenMember" xlink:title="PelacarsenMember" />
    <link:label xlink:type="resource" xlink:label="ions_PelacarsenMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PelacarsenMember_lbl" xml:lang="en-US" id="ions_PelacarsenMember_lbl">Pelacarsen, also known as IONIS-APO(a)-L, AKCEA-APO(a)-L, and TQJ230, is an investigational antisense medicine designed to reduce apolipoprotein(a) in the liver 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="PelacarsenMember" xlink:to="ions_PelacarsenMember_lbl" xlink:title="label: PelacarsenMember to ions_PelacarsenMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PelacarsenMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PelacarsenMember_lbl1" xml:lang="en-US" id="ions_PelacarsenMember_lbl1">Pelacarsen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PelacarsenMember" xlink:to="ions_PelacarsenMember_lbl1" xlink:title="label: PelacarsenMember to ions_PelacarsenMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PelacarsenMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PelacarsenMember_lbl2" xml:lang="en-US" id="ions_PelacarsenMember_lbl2">Pelacarsen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PelacarsenMember" xlink:to="ions_PelacarsenMember_lbl2" xlink:title="label: PelacarsenMember to ions_PelacarsenMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20230331.xsd#ions_RoyaltyRevenueMonetizationAbstract" xlink:label="RoyaltyRevenueMonetizationAbstract" xlink:title="RoyaltyRevenueMonetizationAbstract" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyRevenueMonetizationAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RoyaltyRevenueMonetizationAbstract_lbl1" xml:lang="en-US" id="ions_RoyaltyRevenueMonetizationAbstract_lbl1">Royalty Revenue Monetization [Abstract]</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20230331.xsd#ions_MaximumAmountOfAnnualSalesOnWhichRoyaltyPaymentsArePaid" xlink:label="MaximumAmountOfAnnualSalesOnWhichRoyaltyPaymentsArePaid" xlink:title="MaximumAmountOfAnnualSalesOnWhichRoyaltyPaymentsArePaid" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfAnnualSalesOnWhichRoyaltyPaymentsArePaid_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfAnnualSalesOnWhichRoyaltyPaymentsArePaid_lbl" xml:lang="en-US" id="ions_MaximumAmountOfAnnualSalesOnWhichRoyaltyPaymentsArePaid_lbl">The maximum amount of annual sales on which royalty payments are paid under the royalty purchase agreement.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfAnnualSalesOnWhichRoyaltyPaymentsArePaid_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfAnnualSalesOnWhichRoyaltyPaymentsArePaid_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfAnnualSalesOnWhichRoyaltyPaymentsArePaid_lbl1">Maximum amount of annual sales on which royalty payments are paid</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfAnnualSalesOnWhichRoyaltyPaymentsArePaid_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfAnnualSalesOnWhichRoyaltyPaymentsArePaid_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfAnnualSalesOnWhichRoyaltyPaymentsArePaid_lbl2">Maximum amount of annual sales on which royalty payments are paid</link:label>
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<DESCRIPTION>XBRL TAXONOMY EXTENSION PRESENTATION LINKBASE
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686059712704">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Document and Entity Information - shares<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th"><div>Mar. 31, 2023</div></th>
<th class="th"><div>Apr. 27, 2023</div></th>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
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</tr>
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<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_dei_DocumentType', window );">Document Type</a></td>
<td class="text">10-Q<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="Show.showAR( this, 'defref_dei_AmendmentFlag', window );">Amendment Flag</a></td>
<td class="text">false<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="Show.showAR( this, 'defref_dei_DocumentQuarterlyReport', window );">Document Quarterly 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="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_dei_DocumentPeriodEndDate', window );">Document Period End Date</a></td>
<td class="text">Mar. 31,  2023<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="Show.showAR( this, 'defref_dei_CurrentFiscalYearEndDate', window );">Current Fiscal Year End Date</a></td>
<td class="text">--12-31<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="Show.showAR( this, 'defref_dei_DocumentFiscalYearFocus', window );">Document Fiscal Year Focus</a></td>
<td class="text">2023<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_dei_DocumentFiscalPeriodFocus', window );">Document Fiscal Period Focus</a></td>
<td class="text">Q1<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="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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<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_dei_EntityCommonStockSharesOutstanding', window );">Entity Common Stock, Shares Outstanding</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">143,092,117<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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
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<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_CityAreaCode">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Area code of city</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Cover page.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
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<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
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<td>na</td>
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<td>duration</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_dei_CurrentFiscalYearEndDate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</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_dei_DocumentFiscalPeriodFocus">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
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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_dei_DocumentFiscalYearFocus">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
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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_dei_DocumentPeriodEndDate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
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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_dei_DocumentQuarterlyReport">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Boolean flag that is true only for a form used as an quarterly report.</p></div>
<a href="javascript:void(0);" onclick="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-Q<br> -Number 240<br> -Section 308<br> -Subsection a<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_DocumentQuarterlyReport</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>
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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_dei_DocumentTransitionReport">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
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<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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Name of the City or Town</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Code for the postal or zip code</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Name of the state or province.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Indicate if registrant meets the emerging growth company criteria.</p></div>
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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="Show.toggleNext( this );">+ 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_EntityRegistrantName">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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="Show.toggleNext( this );">+ 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_LocalPhoneNumber">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Local phone number for entity.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Title of a 12(b) registered security.</p></div>
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
</table>
</div>
</body>
</html>
</TEXT>
</DOCUMENT>
<DOCUMENT>
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<SEQUENCE>15
<FILENAME>R2.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
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<head>
<title></title>
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686057002512">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>CONDENSED CONSOLIDATED BALANCE SHEETS - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th"><div>Mar. 31, 2023</div></th>
<th class="th"><div>Dec. 31, 2022</div></th>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsAtCarryingValue', window );">Cash and cash equivalents</a></td>
<td class="nump">$ 309,031<span></span>
</td>
<td class="nump">$ 276,472<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ShortTermInvestments', window );">Short-term investments</a></td>
<td class="nump">2,037,750<span></span>
</td>
<td class="nump">1,710,397<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ContractWithCustomerAssetNetCurrent', window );">Contracts receivable</a></td>
<td class="nump">13,914<span></span>
</td>
<td class="nump">25,538<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_InventoryNet', window );">Inventories</a></td>
<td class="nump">22,200<span></span>
</td>
<td class="nump">22,033<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_OtherAssetsCurrent', window );">Other current assets</a></td>
<td class="nump">159,724<span></span>
</td>
<td class="nump">168,254<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AssetsCurrent', window );">Total current assets</a></td>
<td class="nump">2,542,619<span></span>
</td>
<td class="nump">2,202,694<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentNet', window );">Property, plant and equipment, net</a></td>
<td class="nump">85,158<span></span>
</td>
<td class="nump">74,294<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_OperatingLeaseRightOfUseAsset', window );">Right-of-use assets</a></td>
<td class="nump">179,148<span></span>
</td>
<td class="nump">181,544<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_OtherAssetsNoncurrent', window );">Deposits and other assets</a></td>
<td class="nump">78,296<span></span>
</td>
<td class="nump">75,344<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_Assets', window );">Total assets</a></td>
<td class="nump">2,885,221<span></span>
</td>
<td class="nump">2,533,876<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="Show.showAR( this, 'defref_us-gaap_AccountsPayableCurrent', window );">Accounts payable</a></td>
<td class="nump">10,499<span></span>
</td>
<td class="nump">17,921<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_EmployeeRelatedLiabilitiesCurrent', window );">Accrued compensation</a></td>
<td class="nump">18,160<span></span>
</td>
<td class="nump">49,178<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AccruedLiabilitiesCurrent', window );">Accrued liabilities</a></td>
<td class="nump">112,702<span></span>
</td>
<td class="nump">140,101<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AccruedIncomeTaxesCurrent', window );">Income taxes payable</a></td>
<td class="nump">17,286<span></span>
</td>
<td class="nump">6,249<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityCurrent', window );">Current portion of deferred contract revenue</a></td>
<td class="nump">92,335<span></span>
</td>
<td class="nump">90,577<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_OtherLiabilitiesCurrent', window );">Other current liabilities</a></td>
<td class="nump">8,239<span></span>
</td>
<td class="nump">7,535<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_LiabilitiesCurrent', window );">Total current liabilities</a></td>
<td class="nump">259,221<span></span>
</td>
<td class="nump">311,561<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityNoncurrent', window );">Long-term deferred contract revenue</a></td>
<td class="nump">272,973<span></span>
</td>
<td class="nump">287,768<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="Show.showAR( this, 'defref_ions_LiabilityRelatedToSaleOfFutureRoyaltiesNet', window );">Liability related to sale of future royalties, net</a></td>
<td class="nump">505,081<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="Show.showAR( this, 'defref_us-gaap_OperatingLeaseLiabilityNoncurrent', window );">Long-term lease liabilities</a></td>
<td class="nump">177,000<span></span>
</td>
<td class="nump">178,941<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_LongTermLoansFromBank', window );">Long-term mortgage debt</a></td>
<td class="nump">8,811<span></span>
</td>
<td class="nump">8,847<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_OtherLiabilitiesNoncurrent', window );">Long-term obligations</a></td>
<td class="nump">7,487<span></span>
</td>
<td class="nump">7,126<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_Liabilities', window );">Total liabilities</a></td>
<td class="nump">2,398,651<span></span>
</td>
<td class="nump">1,960,989<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_CommonStockValue', window );">Common stock, $0.001 par value; 300,000,000 shares authorized, 143,022,539 and 142,057,736 shares issued and outstanding at March 31, 2023 (unaudited) and December 31, 2022, respectively</a></td>
<td class="nump">143<span></span>
</td>
<td class="nump">142<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AdditionalPaidInCapitalCommonStock', window );">Additional paid-in capital</a></td>
<td class="nump">2,089,358<span></span>
</td>
<td class="nump">2,059,850<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AccumulatedOtherComprehensiveIncomeLossNetOfTax', window );">Accumulated other comprehensive loss</a></td>
<td class="num">(48,983)<span></span>
</td>
<td class="num">(57,480)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_RetainedEarningsAccumulatedDeficit', window );">Accumulated deficit</a></td>
<td class="num">(1,553,948)<span></span>
</td>
<td class="num">(1,429,625)<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_StockholdersEquity', window );">Total stockholders' equity</a></td>
<td class="nump">486,570<span></span>
</td>
<td class="nump">572,887<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_LiabilitiesAndStockholdersEquity', window );">Total liabilities and stockholders' equity</a></td>
<td class="nump">2,885,221<span></span>
</td>
<td class="nump">2,533,876<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="Show.showAR( this, 'defref_us-gaap_ConvertibleDebtNoncurrent', window );">Convertible senior notes, net</a></td>
<td class="nump">623,025<span></span>
</td>
<td class="nump">622,242<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="Show.showAR( this, 'defref_us-gaap_ConvertibleDebtNoncurrent', window );">Convertible senior notes, net</a></td>
<td class="nump">$ 545,053<span></span>
</td>
<td class="nump">$ 544,504<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_LiabilityRelatedToSaleOfFutureRoyaltiesNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Amount, after accumulated amortization, of the unamortized liability related to the sale of future royalties, pursuant to a royalty purchase agreement, that the Company is entitled to receive under collaboration agreements with Biogen and Novartis. The balance will be amortized over the estimated life of the arrangement using the effective interest rate method.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_LiabilityRelatedToSaleOfFutureRoyaltiesNet</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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=84165509&amp;loc=d3e56426-112766<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
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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_AccruedIncomeTaxesCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126734703&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 https://asc.fasb.org/extlink&amp;oid=126897435&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 https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
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<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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</tr>
</table></div>
</div></td></tr>
</table>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
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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>
</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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=126968391&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 https://asc.fasb.org/extlink&amp;oid=126734703&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 https://asc.fasb.org/extlink&amp;oid=126968391&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 https://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 https://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 https://asc.fasb.org/extlink&amp;oid=126968391&amp;loc=d3e681-108580<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
<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_AdditionalPaidInCapitalCommonStock">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</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_Assets">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ Details</a><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>
</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_AssetsCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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>
<a href="javascript:void(0);" onclick="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 45<br> -Paragraph 1<br> -URI https://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 https://asc.fasb.org/extlink&amp;oid=84165509&amp;loc=d3e56426-112766<br><br>Reference 3: 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 https://asc.fasb.org/extlink&amp;oid=124433192&amp;loc=SL2890621-112765<br><br>Reference 4: 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 https://asc.fasb.org/extlink&amp;oid=126975872&amp;loc=SL124442526-122756<br><br>Reference 5: 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 https://asc.fasb.org/extlink&amp;oid=126975872&amp;loc=SL124442552-122756<br><br>Reference 6: 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 https://asc.fasb.org/extlink&amp;oid=126975872&amp;loc=SL124442526-122756<br><br>Reference 7: 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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 https://asc.fasb.org/extlink&amp;oid=126975872&amp;loc=SL124442552-122756<br><br>Reference 11: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 45<br> -Paragraph 25<br> -Subparagraph (a)<br> -URI https://asc.fasb.org/extlink&amp;oid=116870748&amp;loc=SL6758485-165988<br><br>Reference 12: 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)(B))<br> -URI https://asc.fasb.org/extlink&amp;oid=126975872&amp;loc=SL124442552-122756<br><br>Reference 13: 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 (c)<br> -URI https://asc.fasb.org/extlink&amp;oid=114001798&amp;loc=d3e33918-111571<br><br>Reference 14: http://www.xbrl.org/2009/role/commonPracticeRef<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)(ii))<br> -URI https://asc.fasb.org/extlink&amp;oid=126975872&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 470<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1B<br> -Subparagraph (SX 210.13-02(a)(5))<br> -URI https://asc.fasb.org/extlink&amp;oid=126975872&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 810<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (bb)<br> -URI https://asc.fasb.org/extlink&amp;oid=123419778&amp;loc=d3e5710-111685<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)(iv))<br> -URI https://asc.fasb.org/extlink&amp;oid=126975872&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 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(9))<br> -URI https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br><br>Reference 19: 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 https://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e23780-122690<br><br>Reference 20: 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 https://asc.fasb.org/extlink&amp;oid=126975872&amp;loc=SL124442552-122756<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
<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_CashAndCashEquivalentsAtCarryingValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3044-108585<br><br>Reference 2: http://www.xbrl.org/2003/role/exampleRef<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 https://asc.fasb.org/extlink&amp;oid=124098289&amp;loc=d3e6676-107765<br><br>Reference 3: 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(1))<br> -URI https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126919976&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 https://asc.fasb.org/extlink&amp;oid=126919976&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 https://asc.fasb.org/extlink&amp;oid=126920106&amp;loc=SL49130549-203045<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126919976&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 https://asc.fasb.org/extlink&amp;oid=126919976&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 https://asc.fasb.org/extlink&amp;oid=126920106&amp;loc=SL49130549-203045<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126919976&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 https://asc.fasb.org/extlink&amp;oid=126919976&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 https://asc.fasb.org/extlink&amp;oid=126920106&amp;loc=SL49130549-203045<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_ConvertibleDebtNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EmployeeRelatedLiabilitiesCurrent</td>
</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>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_InventoryNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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(6))<br> -URI https://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 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -Subparagraph (b)<br> -URI https://asc.fasb.org/extlink&amp;oid=124098289&amp;loc=d3e6676-107765<br><br>Reference 3: 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 https://asc.fasb.org/extlink&amp;oid=84165509&amp;loc=d3e56426-112766<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://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="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://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 https://asc.fasb.org/extlink&amp;oid=126897435&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 https://asc.fasb.org/extlink&amp;oid=126734703&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 https://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 https://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 https://asc.fasb.org/extlink&amp;oid=123596393&amp;loc=d3e14064-108612<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://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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https://asc.fasb.org/extlink&amp;oid=126975872&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 https://asc.fasb.org/extlink&amp;oid=123596393&amp;loc=d3e14064-108612<br><br>Reference 20: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 5<br> -URI https://asc.fasb.org/extlink&amp;oid=124098289&amp;loc=d3e6904-107765<br><br>Reference 21: 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 https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
</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_LongTermLoansFromBank">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=126897435&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 https://asc.fasb.org/extlink&amp;oid=126734703&amp;loc=d3e572229-122910<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_OperatingLeaseLiabilityNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Present value of lessee's discounted obligation for lease payments from operating lease, classified as noncurrent.</p></div>
<a href="javascript:void(0);" onclick="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 https://asc.fasb.org/extlink&amp;oid=123391704&amp;loc=SL77918627-209977<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeaseLiabilityNoncurrent</td>
</tr>
<tr>
<td style="padding-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_OperatingLeaseRightOfUseAsset">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=123391704&amp;loc=SL77918627-209977<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_OtherAssetsCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Amount of current assets classified as other.</p></div>
<a href="javascript:void(0);" onclick="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(8))<br> -URI https://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 https://asc.fasb.org/extlink&amp;oid=84165509&amp;loc=d3e56426-112766<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Amount of noncurrent assets classified as other.</p></div>
<a href="javascript:void(0);" onclick="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(17))<br> -URI https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_OtherLiabilitiesCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Amount of liabilities classified as other, due within one year or the normal operating cycle, if longer.</p></div>
<a href="javascript:void(0);" onclick="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 https://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 210.5-02.20)<br> -URI https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherLiabilitiesCurrent</td>
</tr>
<tr>
<td style="padding-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_OtherLiabilitiesNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Amount of liabilities classified as other, due after one year or the normal operating cycle, if longer.</p></div>
<a href="javascript:void(0);" onclick="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 210.5-02.24)<br> -URI https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherLiabilitiesNoncurrent</td>
</tr>
<tr>
<td style="padding-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_PropertyPlantAndEquipmentNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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> -URI https://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 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(a)(8))<br> -URI https://asc.fasb.org/extlink&amp;oid=126734703&amp;loc=d3e572229-122910<br><br>Reference 3: 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 https://asc.fasb.org/extlink&amp;oid=124429447&amp;loc=SL124453093-239630<br><br>Reference 4: 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 https://asc.fasb.org/extlink&amp;oid=84165509&amp;loc=d3e56426-112766<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://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 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(a)(23)(a)(4))<br> -URI https://asc.fasb.org/extlink&amp;oid=126734703&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 944<br> -SubTopic 40<br> -Section 65<br> -Paragraph 2<br> -Subparagraph (h)(2)<br> -URI https://asc.fasb.org/extlink&amp;oid=124501264&amp;loc=SL117420844-207641<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 S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI https://asc.fasb.org/extlink&amp;oid=120397183&amp;loc=d3e187085-122770<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)(i)<br> -URI https://asc.fasb.org/extlink&amp;oid=124501264&amp;loc=SL117420844-207641<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_ShortTermInvestments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Amount of investments including trading securities, available-for-sale securities, held-to-maturity securities, and short-term investments classified as other and current.</p></div>
<a href="javascript:void(0);" onclick="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(4))<br> -URI https://asc.fasb.org/extlink&amp;oid=126897435&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 942<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-03(5))<br> -URI https://asc.fasb.org/extlink&amp;oid=126897435&amp;loc=d3e534808-122878<br><br>Reference 3: http://www.xbrl.org/2009/role/commonPracticeRef<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 https://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 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(a)(1)(g))<br> -URI https://asc.fasb.org/extlink&amp;oid=126734703&amp;loc=d3e572229-122910<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShortTermInvestments</td>
</tr>
<tr>
<td style="padding-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_StockholdersEquity">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://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 https://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 https://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 https://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 https://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 https://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 https://asc.fasb.org/extlink&amp;oid=114001798&amp;loc=d3e33918-111571<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockholdersEquity</td>
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<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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
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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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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>
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<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
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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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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>
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<td></td>
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<td><strong> Data Type:</strong></td>
<td>na</td>
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<td></td>
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686059690432">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>CONDENSED CONSOLIDATED BALANCE SHEETS (Parenthetical) - $ / shares<br></strong></div></th>
<th class="th"><div>Mar. 31, 2023</div></th>
<th class="th"><div>Dec. 31, 2022</div></th>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="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="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="Show.showAR( this, 'defref_us-gaap_CommonStockSharesIssued', window );">Common stock, shares issued (in shares)</a></td>
<td class="nump">143,022,539<span></span>
</td>
<td class="nump">142,057,736<span></span>
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<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_CommonStockSharesOutstanding', window );">Common stock, shares outstanding (in shares)</a></td>
<td class="nump">143,022,539<span></span>
</td>
<td class="nump">142,057,736<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="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="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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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<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
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<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="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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<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">0.125%<span></span>
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<td class="nump">0.125%<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_CommonStockParOrStatedValuePerShare">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CommonStockParOrStatedValuePerShare</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>dtr-types:perShareItemType</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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
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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>xbrli:sharesItemType</td>
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<td>na</td>
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<td>instant</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
</table>
<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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126973232&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 https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
</tr>
<tr>
<td style="padding-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_DebtInstrumentInterestRateStatedPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_LiabilitiesAndStockholdersEquityAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
<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>
<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_us-gaap_StockholdersEquityAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
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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_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0PercentMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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>
</table>
<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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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>
</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;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686056756608">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS - USD ($)<br> shares in Thousands, $ in Thousands</strong></div></th>
<th class="th" colspan="2">3 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Mar. 31, 2023</div></th>
<th class="th"><div>Mar. 31, 2022</div></th>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">$ 130,524<span></span>
</td>
<td class="nump">$ 141,919<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_CostOfGoodsAndServicesSold', window );">Cost of sales</a></td>
<td class="nump">1,343<span></span>
</td>
<td class="nump">4,170<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="Show.showAR( this, 'defref_ions_ResearchDevelopmentAndPatentExpense', window );">Research, development and patent</a></td>
<td class="nump">197,813<span></span>
</td>
<td class="nump">161,126<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_SellingGeneralAndAdministrativeExpense', window );">Selling, general and administrative</a></td>
<td class="nump">45,516<span></span>
</td>
<td class="nump">34,127<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_CostsAndExpenses', window );">Total operating expenses</a></td>
<td class="nump">244,672<span></span>
</td>
<td class="nump">199,423<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_OperatingIncomeLoss', window );">Loss from operations</a></td>
<td class="num">(114,148)<span></span>
</td>
<td class="num">(57,504)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_InvestmentIncomeNet', window );">Investment income</a></td>
<td class="nump">18,627<span></span>
</td>
<td class="nump">1,993<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_InterestExpense', window );">Interest expense</a></td>
<td class="num">(1,608)<span></span>
</td>
<td class="num">(2,122)<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="Show.showAR( this, 'defref_ions_InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties', window );">Interest expense related to sale of future royalties</a></td>
<td class="num">(15,515)<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="Show.showAR( this, 'defref_us-gaap_GainLossOnInvestments', window );">Loss on investments</a></td>
<td class="num">(529)<span></span>
</td>
<td class="num">(6,625)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_OtherNonoperatingIncomeExpense', window );">Other income</a></td>
<td class="nump">230<span></span>
</td>
<td class="nump">187<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest', window );">Loss before income tax expense</a></td>
<td class="num">(112,943)<span></span>
</td>
<td class="num">(64,071)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_IncomeTaxExpenseBenefit', window );">Income tax expense</a></td>
<td class="num">(11,380)<span></span>
</td>
<td class="num">(1,094)<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net loss</a></td>
<td class="num">$ (124,323)<span></span>
</td>
<td class="num">$ (65,165)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasic', window );">Basic net loss per share (in dollars per share)</a></td>
<td class="num">$ (0.87)<span></span>
</td>
<td class="num">$ (0.46)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_EarningsPerShareDiluted', window );">Diluted net loss per share (in dollars per share)</a></td>
<td class="num">$ (0.87)<span></span>
</td>
<td class="num">$ (0.46)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberOfSharesOutstandingBasic', window );">Shares used in computing basic net loss per share (in shares)</a></td>
<td class="nump">142,735<span></span>
</td>
<td class="nump">141,599<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding', window );">Shares used in computing diluted net loss per share (in shares)</a></td>
<td class="nump">142,735<span></span>
</td>
<td class="nump">141,599<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">$ 67,768<span></span>
</td>
<td class="nump">$ 72,285<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">50,247<span></span>
</td>
<td class="nump">53,818<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">6,478<span></span>
</td>
<td class="nump">6,160<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">11,043<span></span>
</td>
<td class="nump">12,307<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueMember', window );">Research and Development Revenue [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="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">62,756<span></span>
</td>
<td class="nump">69,634<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_CollaborativeAgreementRevenueMember', window );">Collaborative Agreement Revenue [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="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">38,334<span></span>
</td>
<td class="nump">49,784<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_EplontersenJointDevelopmentRevenueMember', window );">Eplontersen Joint Development Revenue [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="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">$ 24,422<span></span>
</td>
<td class="nump">$ 19,850<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Amount of interest expense using the effective interest rate method and amortization of issuance costs related to the sale of future royalties.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_InterestExpenseAndAmortizationOfIssuanceCostsRelatedToSaleOfFutureRoyalties</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
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<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_ResearchDevelopmentAndPatentExpense">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_ResearchDevelopmentAndPatentExpense</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_CostOfGoodsAndServicesSold">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=126953954&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CostOfGoodsAndServicesSold</td>
</tr>
<tr>
<td style="padding-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>
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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_CostsAndExpenses">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126953954&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
<td style="padding-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_CostsAndExpensesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
<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_EarningsPerShareBasic">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126732423&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 https://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 https://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22694-107794<br><br>Reference 4: 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-SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(25))<br> -URI https://asc.fasb.org/extlink&amp;oid=126953954&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 https://asc.fasb.org/extlink&amp;oid=126958026&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 https://asc.fasb.org/extlink&amp;oid=126958026&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 https://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=128363288&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 https://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 https://asc.fasb.org/extlink&amp;oid=128363288&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 https://asc.fasb.org/extlink&amp;oid=126958026&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 https://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 https://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 https://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 https://asc.fasb.org/extlink&amp;oid=126958026&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 https://asc.fasb.org/extlink&amp;oid=126732423&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 https://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 https://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 https://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 https://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 https://asc.fasb.org/extlink&amp;oid=126958026&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 https://asc.fasb.org/extlink&amp;oid=126732423&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 https://asc.fasb.org/extlink&amp;oid=126953954&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Amount of realized and unrealized gain (loss) on investment.</p></div>
<a href="javascript:void(0);" onclick="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 https://asc.fasb.org/extlink&amp;oid=126970911&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 https://asc.fasb.org/extlink&amp;oid=126953954&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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126941158&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126953954&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 https://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 https://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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://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 https://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 https://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 https://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 https://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22658-107794<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126953954&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 https://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126953954&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 https://asc.fasb.org/extlink&amp;oid=126953954&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=126901519&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="Show.toggleNext( this );">+ Details</a><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_NonoperatingIncomeExpenseAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
</tr>
<tr>
<td style="padding-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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&amp;loc=d3e8736-108599<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_OtherNonoperatingIncomeExpense">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126953954&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
<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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126920106&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126920106&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 https://asc.fasb.org/extlink&amp;oid=6472922&amp;loc=d3e499488-122856<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126953954&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=126958026&amp;loc=d3e1505-109256<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=126958026&amp;loc=d3e1448-109256<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_WeightedAverageNumberOfSharesOutstandingBasic</td>
</tr>
<tr>
<td style="padding-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_CommercialMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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_CommercialMember</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>
<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>
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<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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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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<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>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></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_srt_ProductOrServiceAxis=us-gaap_ProductMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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>
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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>
</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_srt_ProductOrServiceAxis=ions_LicensingAndOtherRoyaltiesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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>
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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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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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_ResearchAndDevelopmentRevenueMember</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>
</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_srt_ProductOrServiceAxis=ions_CollaborativeAgreementRevenueMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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_CollaborativeAgreementRevenueMember</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>
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<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_EplontersenJointDevelopmentRevenueMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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_EplontersenJointDevelopmentRevenueMember</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>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686063785520">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>CONDENSED CONSOLIDATED STATEMENTS OF COMPREHENSIVE LOSS - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="2">3 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Mar. 31, 2023</div></th>
<th class="th"><div>Mar. 31, 2022</div></th>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_StatementOfIncomeAndComprehensiveIncomeAbstract', window );"><strong>CONSOLIDATED STATEMENTS OF COMPREHENSIVE LOSS [Abstract]</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="Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net loss</a></td>
<td class="num">$ (124,323)<span></span>
</td>
<td class="num">$ (65,165)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent', window );">Unrealized gains (losses) on debt securities, net of tax</a></td>
<td class="nump">8,393<span></span>
</td>
<td class="num">(15,756)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax', window );">Currency translation adjustment</a></td>
<td class="nump">104<span></span>
</td>
<td class="num">(154)<span></span>
</td>
</tr>
<tr class="reu">
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<td class="num">$ (115,826)<span></span>
</td>
<td class="num">$ (81,075)<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_ComprehensiveIncomeNetOfTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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>
<a href="javascript:void(0);" onclick="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 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(22))<br> -URI https://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 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(24))<br> -URI https://asc.fasb.org/extlink&amp;oid=126953954&amp;loc=SL114868664-224227<br><br>Reference 3: 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 5<br> -URI https://asc.fasb.org/extlink&amp;oid=126968391&amp;loc=d3e557-108580<br><br>Reference 4: 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(26))<br> -URI https://asc.fasb.org/extlink&amp;oid=120399700&amp;loc=SL114874048-224260<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 https://asc.fasb.org/extlink&amp;oid=126968391&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 45<br> -Paragraph 1A<br> -Subparagraph (c)<br> -URI https://asc.fasb.org/extlink&amp;oid=126968391&amp;loc=SL7669619-108580<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
<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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=126901519&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="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=126929396&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 https://asc.fasb.org/extlink&amp;oid=126929396&amp;loc=SL4569643-111683<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=126980362&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 https://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 https://asc.fasb.org/extlink&amp;oid=126968391&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 https://asc.fasb.org/extlink&amp;oid=126968391&amp;loc=d3e637-108580<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_StatementOfIncomeAndComprehensiveIncomeAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StatementOfIncomeAndComprehensiveIncomeAbstract</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>
</div>
</body>
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<DESCRIPTION>IDEA: XBRL DOCUMENT
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<head>
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686056660048">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>CONDENSED 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</div></th>
</tr>
<tr class="rc">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="rc">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">(65,165)<span></span>
</td>
<td class="num">(65,165)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">(15,756)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(15,756)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">(154)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(154)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">1,848<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">1,849<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">847<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue', window );">Stock-based compensation expense</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">26,236<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">26,236<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">(9,173)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(9,173)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">(304)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<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="Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance at Mar. 31, 2022</a></td>
<td class="nump">$ 142<span></span>
</td>
<td class="nump">1,983,078<span></span>
</td>
<td class="num">(48,578)<span></span>
</td>
<td class="num">(1,225,068)<span></span>
</td>
<td class="nump">709,574<span></span>
</td>
</tr>
<tr class="rc">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_SharesIssued', window );">Balance (in shares) at Mar. 31, 2022</a></td>
<td class="nump">141,753<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<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="Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance at Dec. 31, 2022</a></td>
<td class="nump">$ 142<span></span>
</td>
<td class="nump">2,059,850<span></span>
</td>
<td class="num">(57,480)<span></span>
</td>
<td class="num">(1,429,625)<span></span>
</td>
<td class="nump">572,887<span></span>
</td>
</tr>
<tr class="rc">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_SharesIssued', window );">Balance (in shares) at Dec. 31, 2022</a></td>
<td class="nump">142,058<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">(124,323)<span></span>
</td>
<td class="num">(124,323)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">8,393<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">8,393<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">104<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">104<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">2,560<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">2,561<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">965<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue', window );">Stock-based compensation expense</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">26,948<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">26,948<span></span>
</td>
</tr>
<tr class="rc">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance at Mar. 31, 2023</a></td>
<td class="nump">$ 143<span></span>
</td>
<td class="nump">$ 2,089,358<span></span>
</td>
<td class="num">$ (48,983)<span></span>
</td>
<td class="num">$ (1,553,948)<span></span>
</td>
<td class="nump">$ 486,570<span></span>
</td>
</tr>
<tr class="rc">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_SharesIssued', window );">Balance (in shares) at Mar. 31, 2023</a></td>
<td class="nump">143,023<span></span>
</td>
<td class="text">&#160;<span></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_us-gaap_AdjustmentsRelatedToTaxWithholdingForShareBasedCompensation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126964447&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 20<br> -Section 55<br> -Paragraph 13<br> -URI https://asc.fasb.org/extlink&amp;oid=126964447&amp;loc=d3e11178-113907<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 35<br> -Paragraph 2<br> -URI https://asc.fasb.org/extlink&amp;oid=126961718&amp;loc=d3e4534-113899<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_IncreaseDecreaseInStockholdersEquityRollForward">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_NetIncomeLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=126901519&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="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=126929396&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 https://asc.fasb.org/extlink&amp;oid=126929396&amp;loc=SL4569643-111683<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=126980362&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 https://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 https://asc.fasb.org/extlink&amp;oid=126968391&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 https://asc.fasb.org/extlink&amp;oid=126968391&amp;loc=d3e637-108580<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126973232&amp;loc=d3e21463-112644<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126973232&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 https://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 https://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 https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ Details</a><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>
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686062368960">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>CONDENSED CONSOLIDATED STATEMENTS OF CASH FLOWS - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="2">3 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Mar. 31, 2023</div></th>
<th class="th"><div>Mar. 31, 2022</div></th>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net loss</a></td>
<td class="num">$ (124,323)<span></span>
</td>
<td class="num">$ (65,165)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract', window );"><strong>Adjustments to reconcile net 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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_Depreciation', window );">Depreciation</a></td>
<td class="nump">2,604<span></span>
</td>
<td class="nump">3,701<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense', window );">Amortization of right-of-use operating lease assets</a></td>
<td class="nump">2,395<span></span>
</td>
<td class="nump">602<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AmortizationOfIntangibleAssets', window );">Amortization of other assets</a></td>
<td class="nump">607<span></span>
</td>
<td class="nump">592<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments', window );">Amortization of premium (discount) on investments, net</a></td>
<td class="num">(5,042)<span></span>
</td>
<td class="nump">4,175<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AmortizationOfFinancingCosts', window );">Amortization of debt issuance costs</a></td>
<td class="nump">1,486<span></span>
</td>
<td class="nump">1,343<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="Show.showAR( this, 'defref_ions_InterestExpenseRelatedToSaleOfFutureRoyalties', window );">Non-cash interest related to sale of future royalties</a></td>
<td class="nump">15,363<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="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensation', window );">Stock-based compensation expense</a></td>
<td class="nump">26,948<span></span>
</td>
<td class="nump">26,236<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_RealizedInvestmentGainsLosses', window );">Loss (gain) on investments</a></td>
<td class="nump">529<span></span>
</td>
<td class="num">(10)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_GainLossOnDispositionOfAssets', window );">Non-cash losses related to disposal of property, plant and equipment</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">527<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ImpairmentOfIntangibleAssetsFinitelived', window );">Non-cash losses related to other assets</a></td>
<td class="nump">445<span></span>
</td>
<td class="nump">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="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInContractWithCustomerAsset', window );">Contracts receivable</a></td>
<td class="nump">11,624<span></span>
</td>
<td class="nump">35,774<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInInventories', window );">Inventories</a></td>
<td class="num">(167)<span></span>
</td>
<td class="nump">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="Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInOtherOperatingAssets', window );">Other current and long-term assets</a></td>
<td class="nump">5,312<span></span>
</td>
<td class="num">(7,222)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInAccruedIncomeTaxesPayable', window );">Income taxes payable</a></td>
<td class="nump">11,037<span></span>
</td>
<td class="nump">865<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInAccountsPayable', window );">Accounts payable</a></td>
<td class="num">(10,295)<span></span>
</td>
<td class="nump">2,878<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInOtherEmployeeRelatedLiabilities', window );">Accrued compensation</a></td>
<td class="num">(31,018)<span></span>
</td>
<td class="num">(22,285)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInOtherCurrentLiabilities', window );">Accrued liabilities and other current liabilities</a></td>
<td class="num">(28,460)<span></span>
</td>
<td class="nump">10,473<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInContractWithCustomerLiability', window );">Deferred contract revenue</a></td>
<td class="num">(13,037)<span></span>
</td>
<td class="num">(25,018)<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_NetCashProvidedByUsedInOperatingActivities', window );">Net cash used in operating activities</a></td>
<td class="num">(133,992)<span></span>
</td>
<td class="num">(31,650)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_PaymentsToAcquireAvailableForSaleSecuritiesDebt', window );">Purchases of short-term investments</a></td>
<td class="num">(688,278)<span></span>
</td>
<td class="num">(462,855)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ProceedsFromSaleAndMaturityOfAvailableForSaleSecurities', window );">Proceeds from sale of short-term investments</a></td>
<td class="nump">374,363<span></span>
</td>
<td class="nump">178,837<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_PaymentsToAcquirePropertyPlantAndEquipment', window );">Purchases of property, plant and equipment</a></td>
<td class="num">(10,472)<span></span>
</td>
<td class="num">(2,705)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_PaymentsToAcquireIntangibleAssets', window );">Acquisition of licenses and other assets, net</a></td>
<td class="num">(1,253)<span></span>
</td>
<td class="num">(826)<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_NetCashProvidedByUsedInInvestingActivities', window );">Net cash used in investing activities</a></td>
<td class="num">(325,640)<span></span>
</td>
<td class="num">(287,549)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOfSharesUnderIncentiveAndShareBasedCompensationPlansIncludingStockOptions', window );">Proceeds from equity, net</a></td>
<td class="nump">2,560<span></span>
</td>
<td class="nump">1,848<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="nump">0<span></span>
</td>
<td class="num">(9,173)<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="Show.showAR( this, 'defref_ions_ProceedsFromSaleOfFutureRoyalties', window );">Proceeds from sale of future royalties</a></td>
<td class="nump">500,000<span></span>
</td>
<td class="nump">0<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="Show.showAR( this, 'defref_ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties', window );">Payments of transaction costs related to sale of future royalties</a></td>
<td class="num">(10,434)<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="Show.showAR( this, 'defref_us-gaap_RepaymentsOfSecuredDebt', window );">Principal payments on mortgage debt</a></td>
<td class="num">(39)<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="Show.showAR( this, 'defref_us-gaap_NetCashProvidedByUsedInFinancingActivities', window );">Net cash provided by (used in) financing activities</a></td>
<td class="nump">492,087<span></span>
</td>
<td class="num">(7,325)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_EffectOfExchangeRateOnCashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsIncludingDisposalGroupAndDiscontinuedOperations', window );">Effects of exchange rates on cash</a></td>
<td class="nump">104<span></span>
</td>
<td class="num">(154)<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect', window );">Net increase (decrease) in cash and cash equivalents</a></td>
<td class="nump">32,559<span></span>
</td>
<td class="num">(326,678)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents', window );">Cash and cash equivalents at beginning of period</a></td>
<td class="nump">276,472<span></span>
</td>
<td class="nump">869,191<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents', window );">Cash and cash equivalents at end of period</a></td>
<td class="nump">309,031<span></span>
</td>
<td class="nump">542,513<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_InterestPaidNet', window );">Interest paid</a></td>
<td class="nump">89<span></span>
</td>
<td class="nump">594<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_IncomeTaxesPaid', window );">Income taxes paid</a></td>
<td class="nump">293<span></span>
</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="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>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_NonCashCapitalAndPatentExpenditures', window );">Amounts accrued for capital and patent expenditures</a></td>
<td class="nump">$ 3,058<span></span>
</td>
<td class="nump">$ 1,344<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_InterestExpenseRelatedToSaleOfFutureRoyalties">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Amount of interest expense using the effective interest rate method related to the sale of future royalties.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_InterestExpenseRelatedToSaleOfFutureRoyalties</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_NonCashCapitalAndPatentExpenditures">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The cash outflow paid to third parties for transaction costs in connection with a monetization transaction of future SPINRAZA and pelacarsen royalties the Company is entitled to under collaboration and licensing agreements.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties</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_ProceedsFromSaleOfFutureRoyalties">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The cash inflow from the sale of future royalties under a royalty purchase agreement.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_ProceedsFromSaleOfFutureRoyalties</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_AccretionAmortizationOfDiscountsAndPremiumsInvestments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Amount of amortization expense attributable to debt issuance costs.</p></div>
<a href="javascript:void(0);" onclick="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 https://asc.fasb.org/extlink&amp;oid=126954810&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 https://asc.fasb.org/extlink&amp;oid=126953954&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 https://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 https://asc.fasb.org/extlink&amp;oid=124435984&amp;loc=d3e28555-108399<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126954810&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 https://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 https://asc.fasb.org/extlink&amp;oid=6388964&amp;loc=d3e16225-109274<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126954810&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 https://asc.fasb.org/extlink&amp;oid=126954810&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 https://asc.fasb.org/extlink&amp;oid=126999549&amp;loc=SL98516268-108586<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3521-108585<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_Depreciation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_EffectOfExchangeRateOnCashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsIncludingDisposalGroupAndDiscontinuedOperations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Amount of increase (decrease) from effect of exchange rate changes on cash and cash equivalents, and cash and cash equivalents restricted to withdrawal or usage; held in foreign currencies; including, but not limited to, 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="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 230<br> -Section 45<br> -Paragraph 1<br> -URI https://asc.fasb.org/extlink&amp;oid=123444420&amp;loc=d3e33268-110906<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectOfExchangeRateOnCashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsIncludingDisposalGroupAndDiscontinuedOperations</td>
</tr>
<tr>
<td style="padding-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_GainLossOnDispositionOfAssets">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Amount of gain (loss) on sale or disposal of property, plant and equipment assets, excluding oil and gas property and timber property.</p></div>
<a href="javascript:void(0);" onclick="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 https://asc.fasb.org/extlink&amp;oid=126954810&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 360<br> -SubTopic 10<br> -Section 45<br> -Paragraph 5<br> -URI https://asc.fasb.org/extlink&amp;oid=126905981&amp;loc=d3e2443-110228<br><br>Reference 3: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 360<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (c)<br> -URI https://asc.fasb.org/extlink&amp;oid=109226691&amp;loc=d3e2941-110230<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_GainLossOnDispositionOfAssets</td>
</tr>
<tr>
<td style="padding-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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126954810&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 https://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16373-109275<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126999549&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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3536-108585<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_IncreaseDecreaseInAccruedIncomeTaxesPayable">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The increase (decrease) during the period in 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="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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInAccruedIncomeTaxesPayable</td>
</tr>
<tr>
<td style="padding-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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126954810&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 https://asc.fasb.org/extlink&amp;oid=126938201&amp;loc=d3e55415-109406<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_IncreaseDecreaseInInventories">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_IncreaseDecreaseInOtherCurrentLiabilities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Amount of increase (decrease) in current liabilities classified as other.</p></div>
<a href="javascript:void(0);" onclick="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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInOtherCurrentLiabilities</td>
</tr>
<tr>
<td style="padding-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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126999549&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 https://asc.fasb.org/extlink&amp;oid=126954810&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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3536-108585<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3521-108585<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3521-108585<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126954810&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 https://asc.fasb.org/extlink&amp;oid=126954810&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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
<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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=126901519&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="Show.toggleNext( this );">+ Details</a><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_OperatingLeaseRightOfUseAssetAmortizationExpense">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_PaymentsRelatedToTaxWithholdingForShareBasedCompensation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3291-108585<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126954810&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 https://asc.fasb.org/extlink&amp;oid=126954810&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 https://asc.fasb.org/extlink&amp;oid=124260329&amp;loc=d3e26853-111562<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3213-108585<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_PaymentsToAcquirePropertyPlantAndEquipment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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>
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<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126954810&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 https://asc.fasb.org/extlink&amp;oid=126954810&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 https://asc.fasb.org/extlink&amp;oid=124260329&amp;loc=d3e26853-111562<br></p></div>
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The cash outflow to repay long-term debt that is wholly or partially secured by collateral. Excludes repayments of tax exempt secured debt.</p></div>
<a href="javascript:void(0);" onclick="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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3291-108585<br></p></div>
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Amount of noncash expense for share-based payment arrangement.</p></div>
<a href="javascript:void(0);" onclick="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 https://asc.fasb.org/extlink&amp;oid=126954810&amp;loc=d3e3602-108585<br></p></div>
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686061896192">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Basis of Presentation<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
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<tr><th class="th"><div>Mar. 31, 2023</div></th></tr>
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<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="Show.showAR( this, 'defref_us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTextBlock', window );">Organization and Basis of Presentation</a></td>
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<div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">1.&#160; Organization and Basis of Presentation</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Organization and Business Activity</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">We incorporated in California on January 10, 1989. In conjunction with our initial public offering, we reorganized as a Delaware corporation in April
    1991. We are a leader in the discovery and development of RNA-targeted 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'; 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'; font-size: 10pt;">We prepared the unaudited interim condensed consolidated financial statements for the three months ended&#160;March 31, 2023 and 2022 on the same basis as the audited financial statements for the year ended December 31, 2022. We included all normal recurring adjustments in the financial statements, which we considered necessary for a fair presentation of our financial position at such dates and our
    operating results and cash flows for those periods. Our operating results for the interim periods may not be indicative of what our operating results will be for the entire year. For more complete financial information, these financial statements, and
    notes thereto, should be read in conjunction with the audited financial statements for the year ended December 31, 2022 included in our Annual
    Report on Form 10-K filed with the Securities and Exchange Commission, or SEC.</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'; font-size: 10pt;">In our condensed consolidated financial statements, we included the accounts of Ionis Pharmaceuticals, Inc. and the consolidated
    results of our wholly owned subsidiary, Akcea Therapeutics, Inc. and its wholly owned subsidiaries (&#8220;we&#8221;, &#8220;us&#8221; or &#8220;our&#8221;).</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'; font-size: 10pt;">We operate as a <span style="-sec-ix-hidden:Fact_d751d8638e404708bbf18fb6bb90a9f5">single</span>
    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_baf534ae803246ddb035eb980683637d">single</span>
    operating segment.</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'; 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; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">We prepare our condensed consolidated financial statements in conformity
      with accounting principles generally accepted in the United States, or </span>U.S., that require us to make estimates and assumptions that affect the amounts reported in our condensed consolidated financial statements and accompanying notes. Actual
    results could differ from our estimates.</div>
<span></span>
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The entire disclosure for organization, consolidation and basis of presentation of financial statements disclosure.</p></div>
<a href="javascript:void(0);" onclick="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 205<br> -URI https://asc.fasb.org/topic&amp;trid=2122149<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -URI https://asc.fasb.org/topic&amp;trid=2197479<br></p></div>
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686149602272">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Significant Accounting Policies<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
</tr>
<tr><th class="th"><div>Mar. 31, 2023</div></th></tr>
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<td class="text">&#160;<span></span>
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<div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">2.&#160; Significant Accounting Policies</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'; font-size: 10pt;">Our significant accounting policies have not changed substantially from those included in our Annual Report on Form 10-K for the year ended
    December 31, 2022, other than as discussed below.</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'; font-size: 10pt; font-weight: bold;">Liability Related to Sale of Future 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'; font-size: 10pt;">In January 2023, we entered into a royalty purchase agreement with Royalty Pharma Investments, or Royalty Pharma, to monetize a portion
    of our future SPINRAZA and pelacarsen royalties we are entitled to under our arrangements with Biogen and Novartis, respectively. Refer to Note 10, <span style="font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;">Liability Related to
      Sale of Future Royalties</span>, for further details on the 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'; font-size: 10pt;">We record upfront payments and milestone payments we receive from the sale of future royalties as a liability, net of transaction costs.
    We record royalty payments made to Royalty Pharma as a reduction of the liability and amortize the transaction costs over the estimated life of the related royalty stream. We account for the associated interest expense under the effective interest rate
    method, while continuing to recognize the full amount of royalty revenue in the period in which the counterparty sells the related product and recognizes the related 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'; font-size: 10pt;">The liability related to the sale of future royalties, effective interest rate and the related interest expense are calculated using our
    current estimate of anticipated future royalty payments under the arrangement, which we periodically reassess based on internal projections and information from our partners who are responsible for commercializing the medicines. If there is a material
    change in our estimate, we will prospectively adjust the liability related to the sale of future royalties, effective interest rate and the related interest expense.</div>

<div style="text-align: left; font-family: Calibri; 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'; font-size: 10pt; font-weight: bold;">Recently Adopted 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'; font-size: 10pt;">We do not expect any recently issued accounting standards to have a material impact to our financial results.</div>
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<div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">3. Supplemental Financial Data</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'; font-size: 10pt; font-weight: bold;">Inventories</div>

<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'; font-size: 10pt;">Our inventory consisted of the following (in thousands):</div>

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


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    <td style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" valign="bottom">

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    <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'; font-size: 10pt; font-weight: bold;">March 31, 2023</div>
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    <td colspan="1" style="text-align: left; 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">December 31, 2022</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; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Raw materials:</div>
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    <td colspan="1" style="vertical-align: bottom; white-space: nowrap;" 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; white-space: nowrap;" 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 19.4pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Raw materials - clinical</div>
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    <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">
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    <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'; font-size: 10pt;">17,356</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; 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">
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    <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'; font-size: 10pt;">17,061</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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  <tr>

    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: justify; text-indent: -18pt; margin-left: 28.4pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Raw materials - commercial</div>
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    <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'; font-size: 10pt;">2,786</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; 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'; font-size: 10pt;">2,699</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; white-space: nowrap;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total raw materials</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'; font-size: 10pt;">20,142</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; 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'; font-size: 10pt;">19,760</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%; white-space: nowrap;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Work in process</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'; font-size: 10pt;">1,840</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%; 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'; font-size: 10pt;">2,109</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; white-space: nowrap;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Finished goods</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'; font-size: 10pt;">218</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; 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'; font-size: 10pt;">164</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; white-space: nowrap;" valign="bottom">
          <div style="text-align: justify; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total inventory</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'; 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'; font-size: 10pt;">22,200</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; 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'; 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'; font-size: 10pt;">22,033</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: Calibri; font-size: 12pt;"><br/>
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<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Accrued Liabilities</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman'; 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', Times, serif; 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'; font-size: 10pt; font-weight: bold;">March 31, 2023</div>
        </td>

    <td colspan="1" style="text-align: left; 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">December 31, 2022</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; white-space: nowrap;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Clinical development expenses</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'; 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'; font-size: 10pt;">85,694</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; 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'; 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'; font-size: 10pt;">116,460</div>
        </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>

    <td style="vertical-align: bottom; width: 76%; white-space: nowrap;" valign="bottom">
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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>

    <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'; font-size: 10pt;">12,704</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%; 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'; font-size: 10pt;">7,945</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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  <tr>

    <td style="vertical-align: bottom; width: 76%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
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        </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'; font-size: 10pt;">4,704</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; 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'; 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>

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    <td style="vertical-align: bottom; width: 76%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
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        </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'; font-size: 10pt;">9,600</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; 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'; font-size: 10pt;">12,198</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>

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    <td style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="text-align: justify; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total accrued liabilities</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%; border-bottom: #000000 double 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">112,702</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; 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'; 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'; font-size: 10pt;">140,101</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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<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">3 Months Ended</th>
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<div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">4.&#160; Collaborative Arrangements and Licensing Agreements</div>

<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'; font-size: 11pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt;">Below, we have included our Biogen and GSK collaborations, which are our
      only collaborations with substantive changes during 2023 from those included in Part IV, Item 15, Note 7 of our audited financial statements
      included in our Annual Report on Form 10-K for the year ended December 31, 2022.</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'; font-size: 10pt; font-style: italic; font-weight: bold;">Biogen</div>

<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'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">We have several strategic collaborations with Biogen focused on using
      antisense technology to advance the treatment of neurological disorders. We developed and licensed to Biogen SPINRAZA, our approved medicine to treat people with spinal muscular atrophy, or SMA. Under our 2013 strategic neurology collaboration,
      Biogen developed QALSODY (tofersen), our recently approved medicine to treat people with superoxide dismutase 1 amyotrophic lateral sclerosis, or SOD1-ALS. We and Biogen are currently developing numerous investigational medicines to treat
      neurodegenerative diseases under these collaborations, including medicines in development to treat people with </span>amyotrophic lateral sclerosis, or ALS<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">, SMA, Angelman
      Syndrome, Alzheimer&#8217;s disease</span><sub style="color: #000000;">&#160;</sub><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">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 </span>March 31, 2023<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">, we have received more than $</span>3.5<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> billion in payments from our Biogen collaborations.</span></div>

<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'; font-size: 10pt;">In the first quarter of 2023, we earned a $10
    million milestone payment from Biogen when we advanced ION582 under our 2012 neurology collaboration. We will recognize revenue as we perform services based on our effort to satisfy our research and development, or R&amp;D, services performance
    obligation relative to the total effort expected to satisfy our performance obligation for ION582. We will achieve the next payment of up to $25
    million if Biogen advances another medicine under our 2012 neurology collaboration.</div>

<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'; font-size: 10pt;">During the three months ended March 31, 2023 and 2022, we earned the following revenue from our relationship with Biogen (in thousands, except percentage amounts):</div>

<div><br/>
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        </td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 31,</div>
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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>

    <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'; font-size: 10pt; font-weight: bold;">2023</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">2022</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: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman'; 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>

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          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">50,247</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">53,818</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: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">20,254</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'; font-size: 10pt;">40,049</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: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">70,501</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">93,867</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: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">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'; 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'; font-size: 10pt;">66</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'; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>

<div style="text-align: left; font-family: Calibri; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">In April 2023, we earned a $16 million
    milestone payment from Biogen when the FDA approved Biogen&#8217;s New Drug Application, or NDA, for QALSODY. We will achieve the next payment of up to $20
    million if Biogen advances a medicine under the 2013 strategic neurology collaboration.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">Our condensed consolidated balance sheets at March 31, 2023 and December 31, 2022<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">&#160;</span>included
    deferred revenue of $340.9 million and $351.2
    million, respectively, from our relationship with Biogen.</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'; font-size: 10pt; font-style: italic; font-weight: bold;">GSK</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">In March 2010, we entered into a collaboration 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. Our collaboration with GSK currently includes bepirovirsen,
      our medicine in development targeting hepatitis B virus, or HBV. We designed this medicine 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</span>. From inception through March 31, 2023, we have received more than $105 million in an upfront payment and payments related to 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'; font-size: 10pt;">In the first quarter of 2023, we earned a $15
    million milestone payment when GSK initiated a Phase 3 program of bepirovirsen. We recognized this milestone payment as R&amp;D revenue in full in the first quarter of 2023 because we did not have any remaining performance obligations related to the
    milestone payment. We will achieve the next payment of $15 million if the FDA accepts an NDA filing of bepirovirsen for review.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">During the three months ended March 31, 2023 and 2022, we earned the following revenue from our relationship with GSK (in thousands, except percentage amounts):</div>

<div><br/>
  </div>

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


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        </td>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 31,</div>
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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">2023</div>
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    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">2022</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>

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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">
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        </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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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>

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          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">11</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'; 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'; 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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<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">We did not have any
    deferred revenue from our relationship with GSK at March 31, 2023 or December 31, 2022.</div>
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The entire disclosure for collaborative arrangements in which the entity is a participant, including a) information about the nature and purpose of such arrangements; b) its rights and obligations thereunder; c) the accounting policy for collaborative arrangements; and d) the income statement classification and amounts attributable to transactions arising from the collaborative arrangement between participants.</p></div>
<a href="javascript:void(0);" onclick="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 808<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI https://asc.fasb.org/extlink&amp;oid=6931272&amp;loc=SL5834143-161434<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 808<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (b)<br> -URI https://asc.fasb.org/extlink&amp;oid=6931272&amp;loc=SL5834143-161434<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 808<br> -URI https://asc.fasb.org/topic&amp;trid=5833765<br></p></div>
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Basic and Diluted Net Loss Per Share<br></strong></div></th>
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<div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">5. Basic and Diluted Net Loss Per Share</div>

<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'; font-size: 10pt; font-weight: bold;">Basic net loss per share</div>

<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'; font-size: 10pt;">We calculated our basic net loss per share for the three months ended&#160;March 31, 2023 and 2022 by dividing our net loss by our weighted-average number of common shares outstanding during the period.</div>

<div><br/>
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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'; font-size: 10pt; font-weight: bold;">Diluted net loss per share</div>

<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'; font-size: 10pt;">For the three months ended&#160;March 31, 2023 and 2022, we incurred a net
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<div><br/>
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    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

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  </tr>


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

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

    <td style="width: auto; vertical-align: top; text-align: left;">
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  </tr>


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

    <td style="width: auto; vertical-align: top; text-align: left;">
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        </td>

  </tr>


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

    <td style="width: auto; vertical-align: top; text-align: left;">
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  </tr>


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

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  </tr>


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

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

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

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<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">Additionally as of March 31, 2023, we had
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The entire disclosure for earnings per share.</p></div>
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686061051360">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Investments<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
</tr>
<tr><th class="th"><div>Mar. 31, 2023</div></th></tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_InvestmentsAbstract', window );"><strong>Investments [Abstract]</strong></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="Show.showAR( this, 'defref_us-gaap_InvestmentTextBlock', window );">Investments</a></td>
<td class="text">
<div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">6.&#160; 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'; font-size: 10pt;">The following table summarizes the contract maturity of the available-for-sale securities we held as of March 31, 2023:</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman', Times, serif; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">74</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'; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">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'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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_f12cc57cfa544d218ac6c26f9aae5797">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'; font-size: 10pt;">3</div>
        </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'; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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">&#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'; font-size: 10pt;">100</div>
        </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'; font-size: 10pt;">%</div>
        </td>

  </tr>


</table>

<div style="text-align: left; font-family: Calibri; 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'; font-size: 10pt;">As illustrated above, at March 31, 2023,
    97 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'; font-size: 10pt;">All of our available-for-sale debt 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; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">We invest in available-for-sale securities</span> with strong credit
    ratings and an investment grade rating at or above A-1, P-1 or F-1 by Standard &amp; Poor&#8217;s, Moody&#8217;s or Fitch, 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'; font-size: 10pt;">At March 31, 2023, we had
    an equity ownership interest of less than 20 percent in seven private companies and three public companies with which we conduct business.</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'; 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', Times, serif; 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="2" style="vertical-align: bottom; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold; text-indent: 6.5pt;">Amortized</div>
        </td>

    <td colspan="1" style="text-align: left; 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="6" 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'; font-size: 10pt; font-weight: bold;">Gross Unrealized</div>
        </td>

    <td colspan="1" style="text-align: left; 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"><span style="text-indent: 0pt;">March 31, 2023</span></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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Cost</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Gains</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Losses</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; 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'; font-size: 10pt;"><span style="text-decoration: underline;">Available-for-sale debt securities:</span></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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">623,940</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">62</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(6,026</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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">617,976</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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">247,629</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'; font-size: 10pt;">69</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'; font-size: 10pt;">(1,283</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'; 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'; font-size: 10pt;">246,415</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'; 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'; font-size: 10pt;">556,394</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">62</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(3,738</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'; 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'; font-size: 10pt;">552,718</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 style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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;" 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'; font-size: 10pt;">57,322</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'; font-size: 10pt;">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>

    <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'; font-size: 10pt;">(498</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'; 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'; font-size: 10pt;">56,828</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: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total debt 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'; font-size: 10pt;">1,485,285</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'; font-size: 10pt;">197</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'; font-size: 10pt;">(11,545</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'; 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'; font-size: 10pt;">1,473,937</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%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Corporate debt 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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">200,661</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'; font-size: 10pt;">336</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'; font-size: 10pt;">(5,205</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'; 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'; font-size: 10pt;">195,792</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'; 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'; font-size: 10pt;">99,635</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">256</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(649</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'; 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'; font-size: 10pt;">99,242</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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Debt securities issued by the U.S. Treasury</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">257,651</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'; font-size: 10pt;">364</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'; font-size: 10pt;">(2,726</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'; 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'; font-size: 10pt;">255,289</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%; 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'; 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: #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'; font-size: 10pt;">14,564</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'; font-size: 10pt;">106</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'; font-size: 10pt;">(182</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'; 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'; font-size: 10pt;">14,488</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;" valign="bottom">
          <div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total debt securities with a maturity of more than one year</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'; font-size: 10pt;">572,511</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'; font-size: 10pt;">1,062</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'; font-size: 10pt;">(8,762</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'; 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'; font-size: 10pt;">564,811</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: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: 27pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total available-for-sale 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">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">2,057,796</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'; 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'; font-size: 10pt;">1,259</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'; 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'; font-size: 10pt;">(20,307</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'; 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'; 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'; font-size: 10pt;">2,038,748</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%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><span style="text-decoration: underline;">Equity securities:</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">&#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>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: 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: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Publicly traded 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">11,897</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(4,508</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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">7,389</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 style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Privately held equity securities included in deposits and other assets (3)</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'; font-size: 10pt;">23,115</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'; font-size: 10pt;">25,001</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'; font-size: 10pt;">(5,125</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'; 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'; font-size: 10pt;">42,991</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: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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">&#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'; font-size: 10pt;">35,012</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'; font-size: 10pt;">25,001</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'; font-size: 10pt;">(9,633</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'; 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'; font-size: 10pt;">50,380</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;" valign="bottom">
          <div style="text-align: left; text-indent: 27pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total available-for-sale debt and equity securities</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'; 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'; font-size: 10pt;">2,092,808</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'; 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'; font-size: 10pt;">26,260</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'; 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'; font-size: 10pt;">(29,940</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'; 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'; 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'; font-size: 10pt;">2,089,128</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="cfttable" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold; text-indent: 6.5pt;">Amortized</div>
        </td>

    <td colspan="1" style="text-align: left; 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="6" 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'; font-size: 10pt; font-weight: bold;">Gross Unrealized</div>
        </td>

    <td colspan="1" style="text-align: left; 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"><span style="text-indent: 0pt;">December 31, 2022</span></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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Cost</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Gains</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Losses</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; 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'; font-size: 10pt;"><span style="text-decoration: underline;">Available-for-sale debt securities:</span></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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">513,790</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">23</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(4,365</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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">509,448</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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">133,585</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'; 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'; font-size: 10pt;">(1,829</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'; 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'; font-size: 10pt;">131,756</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'; 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'; font-size: 10pt;">512,655</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">23</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(5,124</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'; 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'; font-size: 10pt;">507,554</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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">57,484</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'; font-size: 10pt;">18</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'; font-size: 10pt;">(686</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'; 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'; font-size: 10pt;">56,816</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%; 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'; 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'; font-size: 10pt;">6,008</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">&#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'; 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'; font-size: 10pt;">(14</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'; 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'; font-size: 10pt;">5,994</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;" valign="bottom">
          <div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total debt securities with a maturity of one year or less</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'; font-size: 10pt;">1,223,522</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'; font-size: 10pt;">64</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'; font-size: 10pt;">(12,018</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'; 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'; font-size: 10pt;">1,211,568</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%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">227,631</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">14</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(10,143</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'; 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'; font-size: 10pt;">217,502</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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">34,339</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'; 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'; font-size: 10pt;">(1,040</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'; 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'; font-size: 10pt;">33,299</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'; 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'; font-size: 10pt;">245,030</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">(4,109</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'; 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'; font-size: 10pt;">240,921</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 style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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;" 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'; font-size: 10pt;">18,314</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'; font-size: 10pt;">116</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'; font-size: 10pt;">(329</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'; 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'; font-size: 10pt;">18,101</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: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total debt 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'; font-size: 10pt;">525,314</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'; font-size: 10pt;">130</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'; font-size: 10pt;">(15,621</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'; 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'; font-size: 10pt;">509,823</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;" valign="bottom">
          <div style="text-align: left; text-indent: 27pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total available-for-sale debt securities</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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </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'; font-size: 10pt;">1,748,836</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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </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'; font-size: 10pt;">194</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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </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'; font-size: 10pt;">(27,639</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'; 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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </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'; font-size: 10pt;">1,721,391</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%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><span style="text-decoration: underline;">Equity securities:</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">&#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%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Publicly traded equity securities included in other current assets (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'; 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'; font-size: 10pt;">11,897</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'; 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'; 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">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">(1,358</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'; 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'; 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'; font-size: 10pt;">10,539</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%; 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'; font-size: 10pt;">Privately held 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'; font-size: 10pt;">23,115</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'; font-size: 10pt;">17,257</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'; 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'; font-size: 10pt;">40,372</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;" valign="bottom">
          <div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total equity securities</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'; font-size: 10pt;">35,012</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'; font-size: 10pt;">17,257</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'; font-size: 10pt;">(1,358</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'; 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'; font-size: 10pt;">50,911</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: left; text-indent: 27pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total available-for-sale debt 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'; 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'; font-size: 10pt;">1,783,848</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'; 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'; font-size: 10pt;">17,451</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'; 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'; font-size: 10pt;">(28,997</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'; 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'; 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'; font-size: 10pt;">1,772,302</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="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Includes investments classified as cash
            equivalents in our condensed consolidated balance sheets.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

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


  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(2)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Our publicly traded equity securities are
            included in other current assets. We recognize publicly traded equity securities at fair value. In the three months ended&#160;March 31, 2023, we recognized a $3.2
            million unrealized loss in our condensed consolidated statements of operations related to a decrease in the fair value of our investments in publicly traded companies.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

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


  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(3)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">Our privately held equity securities are included in deposits and other assets. We recognize our privately held 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, which are Level 3 inputs<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">. In the three months ended March 31, 2023, we recorded a
              net gain of $</span>2.6<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> million in our condensed
              consolidated statements of operations related to changes in the fair value of our investments in privately held companies.</span></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'; font-size: 10pt;">The following is a summary of our investments we consider to be temporarily impaired at March 31, 2023 (in thousands, except for number of investments):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; 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="6" 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'; font-size: 10pt; font-weight: bold;">Less than 12 Months of</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Temporary Impairment</div>
        </td>

    <td colspan="1" style="text-align: left; 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="6" 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'; font-size: 10pt; font-weight: bold;">More than 12 Months of</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Temporary Impairment</div>
        </td>

    <td colspan="1" style="text-align: left; 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="6" 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'; font-size: 10pt; font-weight: bold;">Total Temporary</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Impairment</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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Number of</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Investments</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Estimated</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Fair Value</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Unrealized</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Losses</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Estimated</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Fair Value</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Unrealized</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Losses</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Estimated</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Fair Value</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Unrealized</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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: 16%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">361</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">434,500</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(1,697</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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">291,713</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(9,534</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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">726,213</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(11,231</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'; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 16%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">68</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'; font-size: 10pt;">138,211</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'; font-size: 10pt;">(424</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'; 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'; font-size: 10pt;">70,965</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'; font-size: 10pt;">(1,508</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'; 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'; font-size: 10pt;">209,176</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'; font-size: 10pt;">(1,932</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'; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 16%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; 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">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">603,444</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(3,873</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'; 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'; font-size: 10pt;">91,448</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(2,591</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'; 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'; font-size: 10pt;">694,892</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(6,464</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'; font-size: 10pt;">)</div>
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  <tr>

    <td style="vertical-align: bottom; width: 16%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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;" 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'; font-size: 10pt;">110</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'; font-size: 10pt;">22,778</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'; font-size: 10pt;">(140</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'; 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'; font-size: 10pt;">32,792</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'; font-size: 10pt;">(540</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'; 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'; font-size: 10pt;">55,570</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'; font-size: 10pt;">(680</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'; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 16%; 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'; font-size: 10pt;">Total temporarily impaired 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">&#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'; font-size: 10pt;">603</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'; 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'; font-size: 10pt;">1,198,933</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'; 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'; font-size: 10pt;">(6,134</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'; 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'; 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'; font-size: 10pt;">486,918</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'; 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'; font-size: 10pt;">(14,173</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'; 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'; 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'; font-size: 10pt;">1,685,851</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'; 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'; font-size: 10pt;">(20,307</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'; font-size: 10pt;">)</div>
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<div style="text-align: left; font-family: Calibri; font-size: 12pt;"><br/>
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<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">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
    rather than underlying credit deterioration for any of the issuers. We believe it is more likely than not that we will be able to hold our debt securities with declines in value to maturity. Therefore, we anticipate full recovery of our debt
    securities&#8217; amortized cost basis at maturity.</div>
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Fair Value Measurements<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
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<div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">7.&#160; Fair Value Measurements</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'; font-size: 10pt;">The following tables present the major security types we held at March 31, 2023 and December 31, 2022 that we regularly measure and
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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>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">At</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 31, 2023</div>
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    <td colspan="1" style="text-align: left; 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>

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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Quoted Prices in</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Active Markets</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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;" 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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    <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 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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">276,352</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">276,352</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">813,768</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'; 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'; font-size: 10pt;">813,768</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-right: 6pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">345,657</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">345,657</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'; 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'; font-size: 10pt;">808,007</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'; font-size: 10pt;">808,007</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'; 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'; 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'; font-size: 10pt;">71,316</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">71,316</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>
            <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Publicly traded equity securities included in other current assets (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'; font-size: 10pt;">7,389</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'; font-size: 10pt;">7,389</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'; 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: 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'; 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'; 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'; font-size: 10pt;">2,322,489</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'; 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'; font-size: 10pt;">1,091,748</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'; 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'; font-size: 10pt;">1,230,741</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', Times, serif; 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">At</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">December 31, 2022</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Quoted Prices in</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Active Markets</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">(Level 1)</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Significant Other</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Observable Inputs</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">211,655</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">211,655</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">726,950</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'; 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'; font-size: 10pt;">726,950</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-right: 6pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">165,055</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">165,055</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'; 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'; font-size: 10pt;">748,475</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'; font-size: 10pt;">748,475</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'; 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'; 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'; font-size: 10pt;">74,917</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">74,917</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: left; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">5,994</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'; 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'; font-size: 10pt;">5,994</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: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Publicly traded equity securities included in other current assets (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'; font-size: 10pt;">10,539</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'; font-size: 10pt;">10,539</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'; 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'; 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'; 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'; font-size: 10pt;">1,943,585</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'; 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'; font-size: 10pt;">970,669</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'; 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'; font-size: 10pt;">972,916</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>

<div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">The following footnotes reference lines in our condensed consolidated balance sheets:</div>

<div><br/>
  </div>

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


  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Included in cash and cash equivalents in our
            condensed consolidated balance sheets.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

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


  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(2)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Included in short-term investments in our
            condensed consolidated balance sheets.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

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


  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(3)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$1.0 million was included in cash and cash equivalents in our condensed consolidated balance sheets, with the difference included in short-term investments in our condensed
            consolidated balance sheets.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

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


  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(4)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Included in other current assets in our
            condensed consolidated balance sheets.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

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


  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(5)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$11.0 million was included in cash and cash equivalents in our condensed consolidated balance sheets, with the difference included in short-term investments in our condensed
            consolidated balance sheets.</div>
        </td>

  </tr>


</table>

<div style="text-align: left; font-family: Calibri; font-size: 12pt;"><br/>
  </div>

<div style="text-align: left; margin-left: 36pt; color: #000000; font-family: 'Times New Roman'; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Our 0.125% Notes and 0% Notes had a fair value of $506.3 million and $578.4 million at March 31, 2023, respectively.
    Our 0.125% Notes and 0% Notes had a
    fair value of $498.9 million and $587.3
    million at December 31, 2022, 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>
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The entire disclosure for the fair value of financial instruments (as defined), including financial assets and financial liabilities (collectively, as defined), and the measurements of those instruments as well as disclosures related to the fair value of non-financial assets and liabilities. Such disclosures about the financial instruments, assets, and liabilities would include: (1) the fair value of the required items together with their carrying amounts (as appropriate); (2) for items for which it is not practicable to estimate fair value, disclosure would include: (a) information pertinent to estimating fair value (including, carrying amount, effective interest rate, and maturity, and (b) the reasons why it is not practicable to estimate fair value; (3) significant concentrations of credit risk including: (a) information about the activity, region, or economic characteristics identifying a concentration, (b) the maximum amount of loss the entity is exposed to based on the gross fair value of the related item, (c) policy for requiring collateral or other security and information as to accessing such collateral or security, and (d) the nature and brief description of such collateral or security; (4) quantitative information about market risks and how such risks are managed; (5) for items measured on both a recurring and nonrecurring basis information regarding the inputs used to develop the fair value measurement; and (6) for items presented in the financial statement for which fair value measurement is elected: (a) information necessary to understand the reasons for the election, (b) discussion of the effect of fair value changes on earnings, (c) a description of [similar groups] items for which the election is made and the relation thereof to the balance sheet, the aggregate carrying value of items included in the balance sheet that are not eligible for the election; (7) all other required (as defined) and desired information.</p></div>
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686061947008">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Stock-based Compensation Expense<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
</tr>
<tr><th class="th"><div>Mar. 31, 2023</div></th></tr>
<tr class="re">
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<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="Show.showAR( this, 'defref_us-gaap_DisclosureOfCompensationRelatedCostsShareBasedPaymentsTextBlock', window );">Stock-based Compensation Expense</a></td>
<td class="text">
<div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">8. 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'; 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 condensed 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'; 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.</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'; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">For the three months ended&#160;March 31, 2023 and 2022, 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: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;">Employee Stock Options:</div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">2023</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">2022</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'; 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'; font-size: 10pt;">3.6</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'; 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'; font-size: 10pt;">1.7</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'; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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'; 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'; font-size: 10pt;">%</div>
        </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'; 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'; font-size: 10pt;">47.5</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'; 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'; font-size: 10pt;">55.2</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'; font-size: 10pt;">%</div>
        </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'; 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'; font-size: 10pt;">6.3 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'; font-size: 10pt;">6.3 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>

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


  <tr>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;">In 2021, our Compensation Committee approved
            an amendment to the 2011 Equity Incentive Plan, or 2011 Plan, and the <span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">2020 Equity Incentive Plan, or</span> 2020 Plan, that increased the contractual term of stock
            options granted under these plans from seven years to ten years for stock options granted on January 1, 2022 and thereafter. We determined that we are unable to rely on our historical exercise data as a basis for estimating the expected
            life of stock options granted to employees following this change because the contractual term changed and we have no other means to reasonably estimate future exercise behavior. We therefore used the simplified method for determining the
            expected life of stock options granted to employees in the three months ended&#160;March 31, 2023 and 2022. Under the simplified method, we calculate the expected term as the average of the time-to-vesting and the contractual life of the options. As we gain additional
            historical information, we will transition to calculating our expected term based on our historical exercise patterns.&#160;</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'; font-size: 10pt; font-style: italic;">ESPP:</div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">2023</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">2022</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'; 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'; font-size: 10pt;">5.2</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'; 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'; 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'; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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'; 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'; font-size: 10pt;">%</div>
        </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'; 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'; font-size: 10pt;">36.7</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'; 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'; font-size: 10pt;">50.2</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'; font-size: 10pt;">%</div>
        </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'; 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'; 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'; 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: Calibri; 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'; font-size: 10pt; font-style: italic;">RSUs:</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'; 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. The RSUs we granted after June 2020 to our board of directors fully vest after one year. The weighted-average grant date fair value of RSUs granted to employees for the three months ended&#160;March 31, 2023 was $39.85
    per share.</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'; font-size: 10pt; font-style: italic;">PRSUs:</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">Beginning in 2020, we added PRSU awards to the compensation for our Chief Executive Officer, Dr. Brett Monia. In 2022, we added PRSU awards to the
    compensation for our other Section 16 officers. Beginning in 2023, we added PRSU awards to the compensation for all executive officers.</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">Under the terms of the PRSUs we granted in 2020 through 2022, <span style="-sec-ix-hidden:Fact_3ea144f70898401099a1731ad0c7e39f"><span style="-sec-ix-hidden:Fact_b531c97d5a394e3f8a5454ecd82ddb93"><span style="-sec-ix-hidden:Fact_b2b6dbe875764e78b9cce0b8464216dd">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 percentto 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; font-family: 'Times New Roman'; font-size: 10pt;">Under the terms of the PRSUs we granted in 2023, 100 percent of the PRSUs may vest at the end of the three-year performance period based on our relative
    TSR as compared to a peer group of companies and as measured at the end of the 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 200 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; font-family: 'Times New Roman'; font-size: 10pt;">We determined the fair value of the PRSUs using a Monte Carlo model because the performance target is based on our relative TSR, which represents a
    market condition. The weighted-average grant date fair value of PRSUs granted to our executive officers for the three months ended&#160;March 31, 2023 and 2022 were $58.99 and $42.28 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'; font-size: 10pt;">The following table summarizes stock-based compensation expense for the three months ended&#160;March 31, 2023 and 2022 (in thousands):</div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt;"><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">2023</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">2022</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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

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          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">160</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">
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        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">19,567</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'; font-size: 10pt;">19,082</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">
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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>

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          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">7,262</div>
        </td>

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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'; font-size: 10pt;">6,994</div>
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  </tr>

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    <td style="vertical-align: bottom; width: 76%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;">26,948</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'; 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'; font-size: 10pt;">26,236</div>
        </td>

    <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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<div style="text-align: left; font-family: Calibri; 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'; font-size: 10pt;">As of March 31, 2023,
    total unrecognized estimated stock-based compensation expense related to non-vested stock options, RSUs and PRSUs was $60.2 million, $79.1 million and $9.5 million, respectively. Our
    actual expenses may differ from these estimates because we will adjust our unrecognized stock-based compensation expense for future forfeitures, including any PRSUs that do not vest. We expect to recognize the cost of stock-based compensation expense
    related to our non-vested stock options, RSUs and PRSUs over a weighted average amortization period of 1.4 years, 1.8 years and 2.2 years, respectively.</div>
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686062263312">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Income Taxes<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
</tr>
<tr><th class="th"><div>Mar. 31, 2023</div></th></tr>
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<div style="text-align: left; text-indent: -36pt; margin-left: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">9.&#160; 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'; font-size: 10pt;">Beginning in 2022, the Tax Cuts and Jobs Act of 2017, or TCJA, requires taxpayers to amortize research and development expenditures over
    five years pursuant to Internal Revenue Code, or IRC, Section 174. Additionally, we expect to reflect the royalty purchase agreement with Royalty Pharma as a taxable sale, requiring us to include the proceeds from the sale, net of currently deductible
    issuance costs, as taxable income in 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'; font-size: 10pt;">We recorded income tax expense of $11.4
    million and $1.1 million for the three months ended March 31, 2023 and 2022, respectively. The increase in income tax expense for the three
    months ended March 31, 2023, compared to the same period in 2022, relates primarily to the impact of the Royalty Pharma transaction. </div>
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The entire disclosure for income taxes. Disclosures may include net deferred tax liability or asset recognized in an enterprise's statement of financial position, net change during the year in the total valuation allowance, approximate tax effect of each type of temporary difference and carryforward that gives rise to a significant portion of deferred tax liabilities and deferred tax assets, utilization of a tax carryback, and tax uncertainties information.</p></div>
<a href="javascript:void(0);" onclick="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 21<br> -URI https://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32857-109319<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 2<br> -Subparagraph (SAB Topic 11.C)<br> -URI https://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330215-122817<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 17<br> -Subparagraph (b)<br> -URI https://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32809-109319<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.5.Q1)<br> -URI https://asc.fasb.org/extlink&amp;oid=122134291&amp;loc=d3e330036-122817<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 14<br> -URI https://asc.fasb.org/extlink&amp;oid=121826272&amp;loc=d3e32705-109319<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 270<br> -Section 50<br> -Paragraph 1<br> -URI https://asc.fasb.org/extlink&amp;oid=6424409&amp;loc=d3e44925-109338<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -URI https://asc.fasb.org/topic&amp;trid=2144680<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 30<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI https://asc.fasb.org/extlink&amp;oid=6424122&amp;loc=d3e41874-109331<br><br>Reference 9: 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 https://asc.fasb.org/extlink&amp;oid=120395691&amp;loc=d3e23780-122690<br></p></div>
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686062223776">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Liability Related to Sale of Future Royalties<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
</tr>
<tr><th class="th"><div>Mar. 31, 2023</div></th></tr>
<tr class="re">
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<td class="text">&#160;<span></span>
</td>
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<td class="text">
<div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">10. Liability Related to Sale of Future 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'; font-size: 10pt;">In January 2023, we entered into a royalty purchase agreement with Royalty Pharma to monetize a portion of our future SPINRAZA and
    pelacarsen royalties we are entitled to under our arrangements with Biogen and Novartis, respectively. As a result, we received an upfront payment of $500
    million and we are eligible to receive up to $625 million in additional milestone payments. Under the terms of the agreement, Royalty Pharma will
    receive 25 percent of our SPINRAZA royalty payments from 2023 through 2027, increasing to 45 percent of royalty payments in 2028, on up to $1.5 billion in annual sales. In
    addition, Royalty Pharma will receive 25 percent of any future royalty payments on pelacarsen, our medicine in development to treat patients
    with elevated lipoprotein(a), or Lp(a), and cardiovascular disease. Royalty Pharma&#8217;s royalty interest in SPINRAZA will revert to us after total SPINRAZA royalty payments to Royalty Pharma reach either $475 million or $550 million, depending on the timing and occurrence of FDA approval of
    pelacarsen.</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'; font-size: 10pt;">We recorded the upfront payment of $500
    million as a liability related to the sale of future royalties, net of transaction costs of $10.4 million, which we are amortizing over the
    estimated life of the arrangement using the effective interest rate method. We recognize royalty revenue in the period in which the counterparty sells the related product and recognizes the related revenue. We record royalty payments made to Royalty
    Pharma as a reduction of the liability.</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'; font-size: 10pt;">We estimate the effective interest rate used to record interest expense under this agreement based on the estimate of future royalty
    payments to Royalty Pharma. As of March 31, 2023, the estimated effective interest rate under the agreement was 13.5 percent.</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'; font-size: 10pt;">The following is a summary of our liability related to sale of future royalties for the three
    months ended March 31, 2023 (in thousands):</div>

<div><br/>
  </div>

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


  <tr>

    <td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;">Proceeds from sale of future royalties</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;">500,000</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%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;">Interest expense related to sale of future royalties</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="font-family: 'Times New Roman'; font-size: 10pt;">15,363</div>
        </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>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;">Liability related to sale of future royalties as of March 31, 2023</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;">515,363</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%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;">Net issuance costs related to sale of future royalties as of March 31, 2023</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="font-family: 'Times New Roman'; font-size: 10pt;">(10,282</div>
        </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="font-family: 'Times New Roman'; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;">Net liability related to sale of future royalties as of March 31, 2023</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="font-family: 'Times New Roman'; 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="font-family: 'Times New Roman'; font-size: 10pt;">505,081</div>
        </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">&#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'; font-size: 10pt;">There are numerous factors, most of which are not within our control, that could materially impact the amount and timing of royalty
    payments from Biogen and Novartis, and result in changes to our estimate of future royalty payments to Royalty Pharma. Such factors include, but are not limited to the commercial sales of SPINRAZA, the regulatory approval and commercial sales of
    pelacarsen, competing products or other significant events.</div>
<span></span>
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686061835120">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Convertible Debt<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
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<td class="text">
<div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">11. 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'; 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; 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'; font-size: 10pt;">At March 31, 2023, we had the following <span style="font-family: Times; font-size: 10pt;">0%</span> Notes outstanding (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', Times, serif; 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="2" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">0% 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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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'; font-size: 10pt;">9.5</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'; 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'; font-size: 10pt;"><span style="-sec-ix-hidden:Fact_edbb9fb31e834f86ad026d22e567df04">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'; 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'; 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'; 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'; 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'; 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'; 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'; 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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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: Calibri; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; 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-family: Times; font-size: 10pt;">0%</span>
    Notes by increasing the effective conversion price on our <span style="font-family: Times; font-size: 10pt;">0%</span> Notes. We increased our
    effective conversion price to $76.39 with the same number of underlying shares as our <span style="font-family: Times; font-size: 10pt;">0%&#160;</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-family: Times; font-size: 10pt;">0%</span> Notes, our note hedges are subject to adjustment. Additionally, our note hedges are exercisable upon conversion of the <span style="font-family: Times; font-size: 10pt;">0%</span> Notes. The note hedges will expire upon maturity of the <span style="font-family: Times; font-size: 10pt;">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-family: Times; font-size: 10pt;">0%</span> Notes. The holders of the <span style="font-family: Times; font-size: 10pt;">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; font-family: 'Times New Roman'; 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 condensed
    consolidated balance sheets. Refer to Part IV, Item 15, Note 1 of our audited financial statements included in our Annual Report on Form 10-K for the year ended December 31, 2022 for our Call Spread accounting policy. 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'; 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; font-family: 'Times New Roman'; font-size: 10pt;">At March 31, 2023, we had the following 0.125%
    Notes outstanding with interest payable semi-annually (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', Times, serif; 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="2" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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'; font-size: 10pt;">3.8</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: top; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><span style="-sec-ix-hidden:Fact_9ad2e8b4fef74d3cab598aa38f5df4fd">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'; 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'; 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'; 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'; 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'; 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'; 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'; 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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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: Calibri; font-size: 12pt;"><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">In conjunction with the issuance of our </span>0.125%<span style="font-family: 'Times New Roman'; font-size: 10pt; 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-family: 'Times New Roman'; font-size: 10pt; color: #000000;">. We increased our effective conversion price to $123.38 with the same number of underlying shares as our </span>0.125%<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> Notes. The call spread cost us $</span>52.6<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> million, of which $</span>108.7<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> million was for the note hedge purchase, offset by $</span>56.1<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> million we received for selling the warrants. Similar to our </span>0.125% Notes<span style="font-family: 'Times New Roman'; font-size: 10pt; 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-family: 'Times New Roman'; font-size: 10pt; color: #000000;">. The note hedges will expire upon maturity of the </span>0.125% Notes<span style="font-family: 'Times New Roman'; font-size: 10pt; 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-family: 'Times New Roman'; font-size: 10pt; color: #000000;">. The holders of
      the </span>0.125% Notes<span style="font-family: 'Times New Roman'; font-size: 10pt; 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'; 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
    condensed consolidated balance sheets. 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'; 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; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">The </span><span style="font-family: Times; font-size: 10pt;">0%</span><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> and </span>0.125%<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> 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 </span>100 percent<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> of the principal amount of the notes to be purchased, plus any accrued and unpaid interest.</span></div>
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<a href="javascript:void(0);" onclick="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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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686061051360">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Legal Proceedings<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
</tr>
<tr><th class="th"><div>Mar. 31, 2023</div></th></tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_CommitmentsAndContingenciesDisclosureAbstract', window );"><strong>Legal Proceedings [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="Show.showAR( this, 'defref_us-gaap_LegalMattersAndContingenciesTextBlock', window );">Legal Proceedings</a></td>
<td class="text">
<div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">12. 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'; 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 we consider the potential loss from any legal proceeding to be probable and we can reasonably estimate the amount, we accrue a liability for the estimated loss. The outcome of
    any proceeding is not determinable in advance. Therefore, we are required to use significant judgment to determine the probability of a loss and whether the amount of the loss is reasonably estimable. Our assessment of a potential liability and the
    amount of accruals we 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'; 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 Shumacher Action. The complaint names Ionis&#8217; board of directors, or the Board, as defendants and names Ionis as a nominal defendant. The Shumacher Action Plaintiff
    asserts a breach of fiduciary duty claim against the Board for awarding and receiving allegedly excessive compensation. The Shumacher Action Plaintiff also asserts an unjust enrichment claim against the non-executive 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. On March 18, 2022, Ionis and the Board moved to dismiss the complaint.
    On May 24, 2022, the parties entered into a Stipulation and Agreement of Compromise, Settlement and Release.</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'; font-size: 10pt;">On May 25, 2022, another purported stockholder of Ionis filed a stockholder derivative complaint also in the Delaware Court of Chancery
    captioned Robert S. Cohen, et al. v. Joseph Loscalzo, et al., C.A. No. 2022-0453, or the Cohen Action. The complaint names the Board as defendants and names Ionis as a nominal defendant. The Cohen Action Plaintiff asserts claims for breach of fiduciary
    duty, unjust enrichment, aiding and abetting breaches of fiduciary duty, and waste against the Board for awarding and receiving allegedly excessive non-executive director compensation for the years 2018, 2019, and 2020. On June 2, 2022, the Cohen
    Action Plaintiff filed a motion to consolidate the related Cohen Action and Shumacher Action. On July 5, 2022, the Court denied the motion to consolidate in favor of the settlement pending in the Shumacher Action.</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'; font-size: 10pt;">On July 18, 2022, Ionis filed a Form 8-K disclosing the pending settlement and attaching the Notice of Pendency of Settlement of Action.
    On September 21, 2022, the Court held a hearing to consider whether the terms of the settlement should be approved, at which hearing the Cohen Action plaintiff objected to the settlement. At the conclusion of the hearing, the Court declined to approve
    the settlement and directed the parties to meet and confer on the issue of the scope of the release. On February 7, 2023, the parties entered into an Amended Stipulation and Agreement of Compromise, Settlement and Release, which folded the Cohen Action
    into the settlement, or the Revised Settlement. The settlement did not have a material impact on our condensed consolidated financial statements. On April 24, 2023, the Court issued an Order and Final Judgment approving the Revised Settlement and
    dismissing the Shumacher and Cohen Actions, and all claims contained therein, with prejudice. The Order does not contain any admission of wrongdoing by any defendant.</div>
<span></span>
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<a href="javascript:void(0);" onclick="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>
<a href="javascript:void(0);" onclick="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 450<br> -URI https://asc.fasb.org/topic&amp;trid=2127136<br></p></div>
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686056860272">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Basis of Presentation (Policies)<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
</tr>
<tr><th class="th"><div>Mar. 31, 2023</div></th></tr>
<tr class="re">
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<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_BasisOfAccountingPolicyPolicyTextBlock', window );">Basis of Presentation</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'; font-size: 10pt;">We prepared the unaudited interim condensed consolidated financial statements for the three months ended&#160;March 31, 2023 and 2022 on the same basis as the audited financial statements for the year ended December 31, 2022. We included all normal recurring adjustments in the financial statements, which we considered necessary for a fair presentation of our financial position at such dates and our
    operating results and cash flows for those periods. Our operating results for the interim periods may not be indicative of what our operating results will be for the entire year. For more complete financial information, these financial statements, and
    notes thereto, should be read in conjunction with the audited financial statements for the year ended December 31, 2022 included in our Annual
    Report on Form 10-K filed with the Securities and Exchange Commission, or SEC.</div>
<span></span>
</td>
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<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ConsolidationPolicyTextBlock', window );">Consolidation</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'; font-size: 10pt;">In our condensed consolidated financial statements, we included the accounts of Ionis Pharmaceuticals, Inc. and the consolidated
    results of our wholly owned subsidiary, Akcea Therapeutics, Inc. and its wholly owned subsidiaries (&#8220;we&#8221;, &#8220;us&#8221; or &#8220;our&#8221;).</div>
<span></span>
</td>
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<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_SegmentReportingPolicyPolicyTextBlock', window );">Segment Information</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'; font-size: 10pt;">We operate as a <span style="-sec-ix-hidden:Fact_d751d8638e404708bbf18fb6bb90a9f5">single</span>
    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_baf534ae803246ddb035eb980683637d">single</span>
    operating segment.</div>
<span></span>
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<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_UseOfEstimates', window );">Use of Estimates</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'; 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; font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">We prepare our condensed consolidated financial statements in conformity
      with accounting principles generally accepted in the United States, or </span>U.S., that require us to make estimates and assumptions that affect the amounts reported in our condensed consolidated financial statements and accompanying notes. Actual
    results could differ from our estimates.</div>
<span></span>
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for basis of accounting, or basis of presentation, used to prepare the financial statements (for example, US Generally Accepted Accounting Principles, Other Comprehensive Basis of Accounting, IFRS).</p></div>
<a href="javascript:void(0);" onclick="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="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>
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for segment reporting.</p></div>
<a href="javascript:void(0);" onclick="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 29<br> -Subparagraph (e)<br> -URI https://asc.fasb.org/extlink&amp;oid=126901519&amp;loc=d3e8864-108599<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 29<br> -Subparagraph (a)<br> -URI https://asc.fasb.org/extlink&amp;oid=126901519&amp;loc=d3e8864-108599<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 https://asc.fasb.org/extlink&amp;oid=126901519&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 29<br> -Subparagraph (c)<br> -URI https://asc.fasb.org/extlink&amp;oid=126901519&amp;loc=d3e8864-108599<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 29<br> -Subparagraph (b)<br> -URI https://asc.fasb.org/extlink&amp;oid=126901519&amp;loc=d3e8864-108599<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 29<br> -URI https://asc.fasb.org/extlink&amp;oid=126901519&amp;loc=d3e8864-108599<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 29<br> -Subparagraph (d)<br> -URI https://asc.fasb.org/extlink&amp;oid=126901519&amp;loc=d3e8864-108599<br></p></div>
<a href="javascript:void(0);" onclick="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="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>
<a href="javascript:void(0);" onclick="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 12<br> -URI https://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6191-108592<br><br>Reference 2: 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 11<br> -URI https://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6161-108592<br><br>Reference 3: 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 9<br> -URI https://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6143-108592<br><br>Reference 4: 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 (b)<br> -URI https://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e5967-108592<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 4<br> -URI https://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6061-108592<br><br>Reference 6: 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 8<br> -URI https://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6132-108592<br><br>Reference 7: 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 (c)<br> -URI https://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e5967-108592<br></p></div>
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686061044912">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Significant Accounting Policies (Policies)<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
</tr>
<tr><th class="th"><div>Mar. 31, 2023</div></th></tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AccountingPoliciesAbstract', window );"><strong>Significant Accounting Policies [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="Show.showAR( this, 'defref_ions_LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock', window );">Liability Related to Sale of Future Royalties</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'; font-size: 10pt; font-weight: bold;">Liability Related to Sale of Future 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'; font-size: 10pt;">In January 2023, we entered into a royalty purchase agreement with Royalty Pharma Investments, or Royalty Pharma, to monetize a portion
    of our future SPINRAZA and pelacarsen royalties we are entitled to under our arrangements with Biogen and Novartis, respectively. Refer to Note 10, <span style="font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;">Liability Related to
      Sale of Future Royalties</span>, for further details on the 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'; font-size: 10pt;">We record upfront payments and milestone payments we receive from the sale of future royalties as a liability, net of transaction costs.
    We record royalty payments made to Royalty Pharma as a reduction of the liability and amortize the transaction costs over the estimated life of the related royalty stream. We account for the associated interest expense under the effective interest rate
    method, while continuing to recognize the full amount of royalty revenue in the period in which the counterparty sells the related product and recognizes the related 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'; font-size: 10pt;">The liability related to the sale of future royalties, effective interest rate and the related interest expense are calculated using our
    current estimate of anticipated future royalty payments under the arrangement, which we periodically reassess based on internal projections and information from our partners who are responsible for commercializing the medicines. If there is a material
    change in our estimate, we will prospectively adjust the liability related to the sale of future royalties, effective interest rate and the related interest 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="Show.showAR( this, 'defref_us-gaap_NewAccountingPronouncementsPolicyPolicyTextBlock', window );">Recently Adopted Accounting Standards</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'; font-size: 10pt; font-weight: bold;">Recently Adopted 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'; font-size: 10pt;">We do not expect any recently issued accounting standards to have a material impact to our financial results.</div>
<span></span>
</td>
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</table>
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Disclosure of inventory accounting policy for liability related to sale of future royalties.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="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="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686061109440">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Basic and Diluted Net Loss Per Share (Policies)<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
</tr>
<tr><th class="th"><div>Mar. 31, 2023</div></th></tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_EarningsPerShareAbstract', window );"><strong>Basic and Diluted Net Loss Per Share [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="Show.showAR( this, 'defref_us-gaap_EarningsPerSharePolicyTextBlock', window );">Basic and Diluted Net Loss Per Share</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'; font-size: 10pt; font-weight: bold;">Basic net 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'; font-size: 10pt;">We calculated our basic net loss per share for the three months ended&#160;March 31, 2023 and 2022 by dividing our net loss by our weighted-average number of common shares outstanding during the period.</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'; font-size: 10pt; font-weight: bold;">Diluted net 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'; font-size: 10pt;">For the three months ended&#160;March 31, 2023 and 2022, 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 from the following would have had an anti-dilutive effect on net loss
    per share:</div>

<div><br/>
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<table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">&#9679;</td>

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">0 percent convertible senior notes, or 0% Notes;</div>
        </td>

  </tr>


</table>

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


  <tr>

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

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

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Note hedges related to the 0% Notes;</div>
        </td>

  </tr>


</table>

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


  <tr>

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

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

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">0.125 percent convertible senior notes, or 0.125% Notes;</div>
        </td>

  </tr>


</table>

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  <tr>

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

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

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Note hedges related to the 0.125% Notes;</div>
        </td>

  </tr>


</table>

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


  <tr>

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

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

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Dilutive stock options;</div>
        </td>

  </tr>


</table>

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


  <tr>

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

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

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

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

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

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

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

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

    <td style="width: auto; vertical-align: top; text-align: left;">
          <div style="color: #000000; font-family: 'Times New Roman'; 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; font-family: 'Times New Roman'; font-size: 10pt;">Additionally as of March 31, 2023, we had
    warrants related to our 0% and 0.125%
    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>
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
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<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=124432515&amp;loc=d3e3630-109257<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686061155280">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Stock-based Compensation Expense (Policies)<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
</tr>
<tr><th class="th"><div>Mar. 31, 2023</div></th></tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DisclosureOfCompensationRelatedCostsSharebasedPaymentsAbstract', window );"><strong>Stock-based Compensation Expense [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
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<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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 condensed 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'; 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
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<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="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="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="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 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (f)(2)(ii)<br> -URI https://asc.fasb.org/extlink&amp;oid=128089324&amp;loc=d3e5070-113901<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (f)(1)<br> -URI https://asc.fasb.org/extlink&amp;oid=128089324&amp;loc=d3e5070-113901<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 50<br> -Paragraph 2<br> -Subparagraph (b)<br> -URI https://asc.fasb.org/extlink&amp;oid=128089324&amp;loc=d3e5070-113901<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (f)(2)(v)<br> -URI https://asc.fasb.org/extlink&amp;oid=128089324&amp;loc=d3e5070-113901<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -URI https://asc.fasb.org/topic&amp;trid=2228938<br><br>Reference 6: http://www.xbrl.org/2003/role/disclosureRef<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.Q6)<br> -URI https://asc.fasb.org/extlink&amp;oid=122041274&amp;loc=d3e301413-122809<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (f)(2)<br> -URI https://asc.fasb.org/extlink&amp;oid=128089324&amp;loc=d3e5070-113901<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<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 https://asc.fasb.org/extlink&amp;oid=128089324&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686061051888">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Supplemental Financial Data (Tables)<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
</tr>
<tr><th class="th"><div>Mar. 31, 2023</div></th></tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_SupplementalFinancialDataAbstract', window );"><strong>Supplemental Financial Data [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="Show.showAR( this, 'defref_us-gaap_ScheduleOfInventoryCurrentTableTextBlock', window );">Inventories</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'; font-size: 10pt; font-weight: bold;">Inventories</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'; 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', Times, serif; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" 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'; font-size: 10pt; font-weight: bold;">March 31, 2023</div>
        </td>

    <td colspan="1" style="text-align: left; 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">December 31, 2022</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; white-space: nowrap;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Raw materials:</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; white-space: nowrap;" 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; white-space: nowrap;" 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 19.4pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Raw materials - clinical</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'; 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'; font-size: 10pt;">17,356</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; 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'; 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'; font-size: 10pt;">17,061</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; white-space: nowrap;" valign="bottom">
          <div style="text-align: justify; text-indent: -18pt; margin-left: 28.4pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Raw materials - commercial</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%; 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'; font-size: 10pt;">2,786</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; 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'; font-size: 10pt;">2,699</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; white-space: nowrap;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total raw materials</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'; font-size: 10pt;">20,142</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; 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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">19,760</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%; white-space: nowrap;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Work in process</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'; font-size: 10pt;">1,840</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%; 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'; font-size: 10pt;">2,109</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; white-space: nowrap;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Finished goods</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'; font-size: 10pt;">218</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; 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'; font-size: 10pt;">164</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; white-space: nowrap;" valign="bottom">
          <div style="text-align: justify; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total inventory</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'; 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'; font-size: 10pt;">22,200</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; 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'; 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'; font-size: 10pt;">22,033</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="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: left; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Accrued Liabilities</div>

<div><br/>
  </div>

<div style="display:none;"><br/></div>
<div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman'; 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', Times, serif; font-size: 10pt; text-align: left; color: #000000; width: 100%;">


  <tr>

    <td style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" 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'; font-size: 10pt; font-weight: bold;">March 31, 2023</div>
        </td>

    <td colspan="1" style="text-align: left; 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">December 31, 2022</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; white-space: nowrap;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Clinical development expenses</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'; 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'; font-size: 10pt;">85,694</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; 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'; 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'; font-size: 10pt;">116,460</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%; white-space: nowrap;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">In-licensing expenses</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'; font-size: 10pt;">12,704</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%; 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'; font-size: 10pt;">7,945</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; white-space: nowrap;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Commercial expenses</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'; font-size: 10pt;">4,704</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; 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">
          <div style="color: #000000; font-family: 'Times New Roman'; 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: 76%; padding-bottom: 2px; white-space: nowrap;" valign="bottom">
          <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Other miscellaneous expenses</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%; 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'; font-size: 10pt;">9,600</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; 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'; font-size: 10pt;">12,198</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; white-space: nowrap;" valign="bottom">
          <div style="text-align: justify; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total accrued liabilities</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686062080736">
<tr>
<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">3 Months Ended</th>
</tr>
<tr><th class="th"><div>Mar. 31, 2023</div></th></tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationsMember', window );">Biogen [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="Show.showAR( this, 'defref_ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems', window );"><strong>Collaborative Arrangements and Licensing Agreements [Abstract]</strong></a></td>
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<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">During the three months ended March 31, 2023 and 2022, we earned the following revenue from our relationship with Biogen (in thousands, except percentage amounts):</div>

<div><br/>
  </div>

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


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    <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'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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>

    <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'; font-size: 10pt; font-weight: bold;">2023</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">2022</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: 76%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">50,247</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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">53,818</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: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">20,254</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'; font-size: 10pt;">40,049</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: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">70,501</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">93,867</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: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">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'; 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'; font-size: 10pt;">66</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'; font-size: 10pt;">%</div>
        </td>

  </tr>


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<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="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="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: left; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;">During the three months ended March 31, 2023 and 2022, we earned the following revenue from our relationship with GSK (in thousands, except percentage amounts):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">2023</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">2022</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: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">15,000</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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>

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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686056624768">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Investments (Tables)<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
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<tr><th class="th"><div>Mar. 31, 2023</div></th></tr>
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<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="Show.showAR( this, 'defref_us-gaap_InvestmentsClassifiedByContractualMaturityDateTableTextBlock', window );">Contract Maturity of Available-for-Sale Securities</a></td>
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<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">The following table summarizes the contract maturity of the available-for-sale securities we held as of March 31, 2023:</div>

<div><br/>
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    <td style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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>

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          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">74</div>
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          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">%</div>
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  <tr>

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          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">After <span style="text-indent: 0pt;">one year</span>
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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'; font-size: 10pt;">23</div>
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          <div style="color: #000000; font-family: 'Times New Roman'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">After <span style="text-indent: 0pt;">two years</span>
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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'; font-size: 10pt;">3</div>
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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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 88%; padding-bottom: 4px;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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">&#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'; font-size: 10pt;">100</div>
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<td class="text">
<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt; font-weight: bold; text-indent: 6.5pt;">Amortized</div>
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    <td colspan="1" style="text-align: left; 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>

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        </td>

    <td colspan="1" style="text-align: left; 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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>

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          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"><span style="text-indent: 0pt;">March 31, 2023</span></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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Cost</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Gains</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Losses</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Fair Value</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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          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><span style="text-decoration: underline;">Available-for-sale debt securities:</span></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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">623,940</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">62</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(6,026</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'; 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'; 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'; font-size: 10pt;">617,976</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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">247,629</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'; font-size: 10pt;">69</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'; font-size: 10pt;">(1,283</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'; 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'; font-size: 10pt;">246,415</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'; 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'; font-size: 10pt;">556,394</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">62</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(3,738</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'; 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'; font-size: 10pt;">552,718</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 style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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;" 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'; font-size: 10pt;">57,322</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'; font-size: 10pt;">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>

    <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'; font-size: 10pt;">(498</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'; 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'; font-size: 10pt;">56,828</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: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total debt 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'; font-size: 10pt;">1,485,285</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'; font-size: 10pt;">197</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'; font-size: 10pt;">(11,545</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'; 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'; font-size: 10pt;">1,473,937</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%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Corporate debt 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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">200,661</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'; font-size: 10pt;">336</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'; font-size: 10pt;">(5,205</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'; 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'; font-size: 10pt;">195,792</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'; 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'; font-size: 10pt;">99,635</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">256</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(649</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'; 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'; font-size: 10pt;">99,242</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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Debt securities issued by the U.S. Treasury</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">257,651</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'; font-size: 10pt;">364</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'; font-size: 10pt;">(2,726</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'; 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'; font-size: 10pt;">255,289</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%; 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'; 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: #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'; font-size: 10pt;">14,564</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'; font-size: 10pt;">106</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'; font-size: 10pt;">(182</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'; 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'; font-size: 10pt;">14,488</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;" valign="bottom">
          <div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total debt securities with a maturity of more than one year</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'; font-size: 10pt;">572,511</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'; font-size: 10pt;">1,062</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'; font-size: 10pt;">(8,762</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'; 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'; font-size: 10pt;">564,811</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: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: 27pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total available-for-sale 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">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">2,057,796</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'; 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'; font-size: 10pt;">1,259</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'; 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'; font-size: 10pt;">(20,307</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'; 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'; 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'; font-size: 10pt;">2,038,748</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%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><span style="text-decoration: underline;">Equity securities:</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">&#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>

    <td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: 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: 52%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Publicly traded 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">11,897</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(4,508</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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">7,389</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 style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Privately held equity securities included in deposits and other assets (3)</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'; font-size: 10pt;">23,115</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'; font-size: 10pt;">25,001</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'; font-size: 10pt;">(5,125</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'; 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'; font-size: 10pt;">42,991</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: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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">&#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'; font-size: 10pt;">35,012</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'; font-size: 10pt;">25,001</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'; font-size: 10pt;">(9,633</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'; 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'; font-size: 10pt;">50,380</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;" valign="bottom">
          <div style="text-align: left; text-indent: 27pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total available-for-sale debt and equity securities</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'; 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'; font-size: 10pt;">2,092,808</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'; 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'; font-size: 10pt;">26,260</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'; 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'; font-size: 10pt;">(29,940</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'; 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'; 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'; font-size: 10pt;">2,089,128</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="cfttable" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold; text-indent: 6.5pt;">Amortized</div>
        </td>

    <td colspan="1" style="text-align: left; 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="6" 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'; font-size: 10pt; font-weight: bold;">Gross Unrealized</div>
        </td>

    <td colspan="1" style="text-align: left; 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"><span style="text-indent: 0pt;">December 31, 2022</span></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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Cost</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Gains</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Losses</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; 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'; font-size: 10pt;"><span style="text-decoration: underline;">Available-for-sale debt securities:</span></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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">513,790</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">23</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(4,365</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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">509,448</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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">133,585</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'; 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'; font-size: 10pt;">(1,829</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'; 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'; font-size: 10pt;">131,756</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'; 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'; font-size: 10pt;">512,655</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">23</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(5,124</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'; 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'; font-size: 10pt;">507,554</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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">57,484</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'; font-size: 10pt;">18</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'; font-size: 10pt;">(686</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'; 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'; font-size: 10pt;">56,816</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%; 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'; 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'; font-size: 10pt;">6,008</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">&#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'; 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'; font-size: 10pt;">(14</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'; 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'; font-size: 10pt;">5,994</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;" valign="bottom">
          <div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total debt securities with a maturity of one year or less</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'; font-size: 10pt;">1,223,522</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'; font-size: 10pt;">64</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'; font-size: 10pt;">(12,018</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'; 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'; font-size: 10pt;">1,211,568</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%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">227,631</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">14</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(10,143</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'; 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'; font-size: 10pt;">217,502</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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">34,339</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'; 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'; font-size: 10pt;">(1,040</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'; 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'; font-size: 10pt;">33,299</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'; 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'; font-size: 10pt;">245,030</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">(4,109</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'; 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'; font-size: 10pt;">240,921</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 style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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;" 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'; font-size: 10pt;">18,314</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'; font-size: 10pt;">116</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'; font-size: 10pt;">(329</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'; 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'; font-size: 10pt;">18,101</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: 2px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total debt 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'; font-size: 10pt;">525,314</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'; font-size: 10pt;">130</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'; font-size: 10pt;">(15,621</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'; 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'; font-size: 10pt;">509,823</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;" valign="bottom">
          <div style="text-align: left; text-indent: 27pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total available-for-sale debt securities</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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </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'; font-size: 10pt;">1,748,836</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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </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'; font-size: 10pt;">194</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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </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'; font-size: 10pt;">(27,639</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'; 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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </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'; font-size: 10pt;">1,721,391</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%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"><span style="text-decoration: underline;">Equity securities:</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">&#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%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Publicly traded equity securities included in other current assets (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'; 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'; font-size: 10pt;">11,897</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'; 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'; 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">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">(1,358</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'; 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'; 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'; font-size: 10pt;">10,539</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%; 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'; font-size: 10pt;">Privately held 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'; font-size: 10pt;">23,115</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'; font-size: 10pt;">17,257</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'; 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'; font-size: 10pt;">40,372</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;" valign="bottom">
          <div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total equity securities</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'; font-size: 10pt;">35,012</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'; font-size: 10pt;">17,257</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'; font-size: 10pt;">(1,358</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'; 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'; font-size: 10pt;">50,911</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: left; text-indent: 27pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Total available-for-sale debt 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'; 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'; font-size: 10pt;">1,783,848</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'; 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'; font-size: 10pt;">17,451</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'; 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'; font-size: 10pt;">(28,997</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'; 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'; 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'; font-size: 10pt;">1,772,302</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="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;">


  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Includes investments classified as cash
            equivalents in our condensed consolidated balance sheets.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

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


  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(2)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Our publicly traded equity securities are
            included in other current assets. We recognize publicly traded equity securities at fair value. In the three months ended&#160;March 31, 2023, we recognized a $3.2
            million unrealized loss in our condensed consolidated statements of operations related to a decrease in the fair value of our investments in publicly traded companies.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

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


  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(3)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;"><span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">Our privately held equity securities are included in deposits and other assets. We recognize our privately held 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, which are Level 3 inputs<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">. In the three months ended March 31, 2023, we recorded a
              net gain of $</span>2.6<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> million in our condensed
              consolidated statements of operations related to changes in the fair value of our investments in privately held companies.</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="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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">The following is a summary of our investments we consider to be temporarily impaired at March 31, 2023 (in thousands, except for number of investments):</div>

<div><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; 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="6" 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'; font-size: 10pt; font-weight: bold;">Less than 12 Months of</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Temporary Impairment</div>
        </td>

    <td colspan="1" style="text-align: left; 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="6" 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'; font-size: 10pt; font-weight: bold;">More than 12 Months of</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Temporary Impairment</div>
        </td>

    <td colspan="1" style="text-align: left; 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="6" 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'; font-size: 10pt; font-weight: bold;">Total Temporary</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Impairment</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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Number of</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Investments</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Estimated</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Fair Value</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Unrealized</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Losses</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Estimated</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Fair Value</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Unrealized</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Losses</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Estimated</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Fair Value</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Unrealized</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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: 16%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">361</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">434,500</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(1,697</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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">291,713</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(9,534</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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">726,213</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(11,231</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'; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 16%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">68</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'; font-size: 10pt;">138,211</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'; font-size: 10pt;">(424</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'; 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'; font-size: 10pt;">70,965</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'; font-size: 10pt;">(1,508</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'; 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'; font-size: 10pt;">209,176</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'; font-size: 10pt;">(1,932</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'; font-size: 10pt;">)</div>
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  <tr>

    <td style="vertical-align: bottom; width: 16%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Debt securities issued by the U.S. Treasury</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'; 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">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">603,444</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(3,873</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'; 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'; font-size: 10pt;">91,448</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(2,591</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'; 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'; font-size: 10pt;">694,892</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(6,464</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'; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 16%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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;" 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'; font-size: 10pt;">110</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'; font-size: 10pt;">22,778</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'; font-size: 10pt;">(140</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'; 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'; font-size: 10pt;">32,792</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'; font-size: 10pt;">(540</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'; 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'; font-size: 10pt;">55,570</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'; font-size: 10pt;">(680</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'; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 16%; 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'; font-size: 10pt;">Total temporarily impaired 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">&#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'; font-size: 10pt;">603</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'; 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'; font-size: 10pt;">1,198,933</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'; 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'; font-size: 10pt;">(6,134</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'; 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'; 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'; font-size: 10pt;">486,918</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'; 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'; font-size: 10pt;">(14,173</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'; 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'; 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'; font-size: 10pt;">1,685,851</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'; 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'; font-size: 10pt;">(20,307</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'; font-size: 10pt;">)</div>
        </td>

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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Tabular disclosure of maturities of an entity's investments as well as any other information pertinent to the investments.</p></div>
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">- Definition</a><div><p>Tabular disclosure of investments in an unrealized loss position for which other-than-temporary impairments have not been recognized in earnings (including investments for which a portion of an other-than-temporary impairment has been recognized in other comprehensive income), including: (a) the aggregate related fair value of investments with unrealized losses, (b) the aggregate amount of unrealized losses (that is, the amount by which amortized cost basis exceeds fair value).</p></div>
<a href="javascript:void(0);" onclick="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 6<br> -URI https://asc.fasb.org/extlink&amp;oid=126970911&amp;loc=d3e27290-111563<br></p></div>
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Tabular disclosure of unrealized gains and losses on investments.</p></div>
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686062365584">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Fair Value Measurements (Tables)<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
</tr>
<tr><th class="th"><div>Mar. 31, 2023</div></th></tr>
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<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_FairValueDisclosuresAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></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="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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">The following tables present the major security types we held at March 31, 2023 and December 31, 2022 that we regularly measure and
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<div><br/>
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          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">At</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 31, 2023</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Quoted Prices in</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Active Markets</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">(Level 1)</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Significant Other</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Observable Inputs</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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>

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  <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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">276,352</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">276,352</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">813,768</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'; 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'; font-size: 10pt;">813,768</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-right: 6pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">345,657</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">345,657</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'; 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'; font-size: 10pt;">808,007</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'; font-size: 10pt;">808,007</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'; 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'; 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'; font-size: 10pt;">71,316</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">71,316</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>
            <div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Publicly traded equity securities included in other current assets (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'; font-size: 10pt;">7,389</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'; font-size: 10pt;">7,389</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'; 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: 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'; 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'; 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'; font-size: 10pt;">2,322,489</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'; 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'; font-size: 10pt;">1,091,748</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'; 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'; font-size: 10pt;">1,230,741</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', Times, serif; 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">At</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">December 31, 2022</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Quoted Prices in</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Active Markets</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">(Level 1)</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">Significant Other</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Observable Inputs</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">211,655</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">211,655</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">726,950</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'; 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'; font-size: 10pt;">726,950</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-right: 6pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">165,055</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">165,055</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'; 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'; font-size: 10pt;">748,475</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'; font-size: 10pt;">748,475</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'; 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'; 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'; font-size: 10pt;">74,917</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">74,917</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: left; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">5,994</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'; 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'; font-size: 10pt;">5,994</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: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Publicly traded equity securities included in other current assets (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'; font-size: 10pt;">10,539</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'; font-size: 10pt;">10,539</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'; 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'; 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'; 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'; font-size: 10pt;">1,943,585</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'; 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'; font-size: 10pt;">970,669</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'; 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'; font-size: 10pt;">972,916</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>

<div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">The following footnotes reference lines in our condensed consolidated balance sheets:</div>

<div><br/>
  </div>

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


  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(1)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Included in cash and cash equivalents in our
            condensed consolidated balance sheets.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

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


  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(2)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Included in short-term investments in our
            condensed consolidated balance sheets.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

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


  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(3)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$1.0 million was included in cash and cash equivalents in our condensed consolidated balance sheets, with the difference included in short-term investments in our condensed
            consolidated balance sheets.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

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


  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(4)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Included in other current assets in our
            condensed consolidated balance sheets.</div>
        </td>

  </tr>


</table>

<div><br/>
  </div>

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


  <tr>

    <td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">(5)</td>

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$11.0 million was included in cash and cash equivalents in our condensed consolidated balance sheets, with the difference included in short-term investments in our condensed
            consolidated balance sheets.</div>
        </td>

  </tr>


</table>
<span></span>
</td>
</tr>
</table>
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686061978960">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Stock-based Compensation Expense (Tables)<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
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<tr><th class="th"><div>Mar. 31, 2023</div></th></tr>
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<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="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: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;">Employee Stock Options:</div>

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        </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'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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>

  </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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">2023</div>
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    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">2022</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; 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'; font-size: 10pt;">Risk-free interest rate</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'; font-size: 10pt;">3.6</div>
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          <div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;">1.7</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'; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Dividend yield</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'; 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'; font-size: 10pt;">0.0</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'; font-size: 10pt;">%</div>
        </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'; font-size: 10pt;">Volatility</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'; font-size: 10pt;">47.5</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'; 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'; font-size: 10pt;">55.2</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'; font-size: 10pt;">%</div>
        </td>

  </tr>

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    <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'; font-size: 10pt;">Expected life*</div>
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    <td colspan="1" style="vertical-align: bottom;" valign="bottom">&#160;</td>

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          <div style="text-align: right; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">6.3 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'; font-size: 10pt;">6.3 years</div>
        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; white-space: nowrap;" valign="bottom">&#160;</td>

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</table>

<div><br/>
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  <tr>

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

    <td style="width: auto; vertical-align: top; text-align: justify;">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;">In 2021, our Compensation Committee approved
            an amendment to the 2011 Equity Incentive Plan, or 2011 Plan, and the <span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">2020 Equity Incentive Plan, or</span> 2020 Plan, that increased the contractual term of stock
            options granted under these plans from seven years to ten years for stock options granted on January 1, 2022 and thereafter. We determined that we are unable to rely on our historical exercise data as a basis for estimating the expected
            life of stock options granted to employees following this change because the contractual term changed and we have no other means to reasonably estimate future exercise behavior. We therefore used the simplified method for determining the
            expected life of stock options granted to employees in the three months ended&#160;March 31, 2023 and 2022. Under the simplified method, we calculate the expected term as the average of the time-to-vesting and the contractual life of the options. As we gain additional
            historical information, we will transition to calculating our expected term based on our historical exercise patterns.&#160;</div>
        </td>

  </tr>


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

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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>

  </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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">2023</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">2022</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'; 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'; font-size: 10pt;">5.2</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'; 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'; 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'; font-size: 10pt;">%</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: bottom; width: 76%;" valign="bottom">
          <div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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'; 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'; font-size: 10pt;">%</div>
        </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'; 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'; font-size: 10pt;">36.7</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'; 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'; font-size: 10pt;">50.2</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'; font-size: 10pt;">%</div>
        </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'; 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'; 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'; 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>
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<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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'; font-size: 10pt;">The following table summarizes stock-based compensation expense for the three months ended&#160;March 31, 2023 and 2022 (in thousands):</div>

<div style="display:none;"><br/></div>
<div style="text-align: justify; text-indent: 36pt;"><br/>
  </div>

<table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">Three Months Ended</div>
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">March 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; white-space: nowrap;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">2023</div>
        </td>

    <td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;">2022</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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">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">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">160</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: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Research, development and patent 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">&#160;</td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">19,567</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'; font-size: 10pt;">19,082</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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;">Selling, general and administrative expense</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'; font-size: 10pt;">7,262</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'; font-size: 10pt;">6,994</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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;">26,948</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'; 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'; font-size: 10pt;">26,236</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>


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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686062275520">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Liability Related to Sale of Future Royalties (Tables)<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
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<tr><th class="th"><div>Mar. 31, 2023</div></th></tr>
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<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_OtherLiabilitiesDisclosureAbstract', window );"><strong>Liability Related to Sale of Future Royalties [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="Show.showAR( this, 'defref_us-gaap_OtherNoncurrentLiabilitiesTableTextBlock', window );">Liability Related to Sale of Future Royalties</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'; font-size: 10pt;">The following is a summary of our liability related to sale of future royalties for the three
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<div><br/>
  </div>

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


  <tr>

    <td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;">Proceeds from sale of future royalties</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;">500,000</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%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;">Interest expense related to sale of future royalties</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="font-family: 'Times New Roman'; font-size: 10pt;">15,363</div>
        </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>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;">Liability related to sale of future royalties as of March 31, 2023</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">&#160;</td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="font-family: 'Times New Roman'; font-size: 10pt;">515,363</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%; padding-bottom: 2px;" valign="bottom">
          <div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;">Net issuance costs related to sale of future royalties as of March 31, 2023</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="font-family: 'Times New Roman'; font-size: 10pt;">(10,282</div>
        </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="font-family: 'Times New Roman'; font-size: 10pt;">)</div>
        </td>

  </tr>

  <tr>

    <td style="vertical-align: top; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;">Net liability related to sale of future royalties as of March 31, 2023</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="font-family: 'Times New Roman'; 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="font-family: 'Times New Roman'; font-size: 10pt;">505,081</div>
        </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">&#160;</td>

  </tr>


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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686056914784">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Convertible Debt (Tables)<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
</tr>
<tr><th class="th"><div>Mar. 31, 2023</div></th></tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="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="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'; font-size: 10pt;">At March 31, 2023, we had the following <span style="font-family: Times; font-size: 10pt;">0%</span> Notes outstanding (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', Times, serif; 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="2" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">0% 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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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'; font-size: 10pt;">9.5</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'; 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'; font-size: 10pt;"><span style="-sec-ix-hidden:Fact_edbb9fb31e834f86ad026d22e567df04">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'; 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'; 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'; 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'; 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'; 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'; 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'; 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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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>
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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="Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentMember', window );">0.125% Notes [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="Show.showAR( this, 'defref_ions_ConvertibleNotesDisclosureLineItems', window );"><strong>Convertible Notes [Abstract]</strong></a></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="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'; font-size: 10pt;">At March 31, 2023, we had the following 0.125%
    Notes outstanding with interest payable semi-annually (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', Times, serif; 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="2" style="vertical-align: top; border-bottom: #000000 solid 2px;" valign="bottom">
          <div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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'; font-size: 10pt;">3.8</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: top; background-color: #CCEEFF;" valign="bottom">
          <div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"><span style="-sec-ix-hidden:Fact_9ad2e8b4fef74d3cab598aa38f5df4fd">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'; 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'; 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'; 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'; 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'; 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'; 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'; 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'; 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'; font-size: 10pt;">$</div>
        </td>

    <td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom">
          <div style="color: #000000; font-family: 'Times New Roman'; 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'; 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">
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        </td>

    <td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; white-space: nowrap;" valign="bottom">&#160;</td>

  </tr>


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<span></span>
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<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">- Definition</a><div><p>Tabular disclosure of convertible debt instrument. Includes, but is not limited to, principal amount and amortized premium or discount.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="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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<td><strong> Name:</strong></td>
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<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes0125PercentMember</td>
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686061155280">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Basis of Presentation (Details)<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
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<tr><th class="th">
<div>Mar. 31, 2023 </div>
<div>Segment</div>
</th></tr>
<tr class="re">
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<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_NumberOfOperatingSegments', window );">Number of operating segments</a></td>
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<div style="display: none;">
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126901519&amp;loc=d3e8672-108599<br></p></div>
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="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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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686056791056">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Supplemental Financial Data, Inventories (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th"><div>Mar. 31, 2023</div></th>
<th class="th"><div>Dec. 31, 2022</div></th>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_InventoryNetAbstract', window );"><strong>Inventory [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="Show.showAR( this, 'defref_us-gaap_InventoryRawMaterials', window );">Raw materials</a></td>
<td class="nump">$ 20,142<span></span>
</td>
<td class="nump">$ 19,760<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_InventoryWorkInProcess', window );">Work in process</a></td>
<td class="nump">1,840<span></span>
</td>
<td class="nump">2,109<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_InventoryFinishedGoods', window );">Finished goods</a></td>
<td class="nump">218<span></span>
</td>
<td class="nump">164<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_InventoryNet', window );">Total inventory</a></td>
<td class="nump">22,200<span></span>
</td>
<td class="nump">22,033<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_InventoryNetAbstract', window );"><strong>Inventory [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="Show.showAR( this, 'defref_us-gaap_InventoryRawMaterials', window );">Raw materials</a></td>
<td class="nump">17,356<span></span>
</td>
<td class="nump">17,061<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_InventoryNetAbstract', window );"><strong>Inventory [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="Show.showAR( this, 'defref_us-gaap_InventoryRawMaterials', window );">Raw materials</a></td>
<td class="nump">$ 2,786<span></span>
</td>
<td class="nump">$ 2,699<span></span>
</td>
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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">
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<a href="javascript:void(0);" onclick="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="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 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(6)(a)(1))<br> -URI https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="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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<td>instant</td>
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<a href="javascript:void(0);" onclick="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="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(6))<br> -URI https://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 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -Subparagraph (b)<br> -URI https://asc.fasb.org/extlink&amp;oid=124098289&amp;loc=d3e6676-107765<br><br>Reference 3: 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 https://asc.fasb.org/extlink&amp;oid=84165509&amp;loc=d3e56426-112766<br></p></div>
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="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="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="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 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(6)(a)(4))<br> -URI https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="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="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="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 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(6)(a)(3))<br> -URI https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="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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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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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</div>
</body>
</html>
</TEXT>
</DOCUMENT>
<DOCUMENT>
<TYPE>XML
<SEQUENCE>46
<FILENAME>R33.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="include/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;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686059889616">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Supplemental Financial Data, Accrued Liabilities (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th"><div>Mar. 31, 2023</div></th>
<th class="th"><div>Dec. 31, 2022</div></th>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="Show.showAR( this, 'defref_ions_AccruedClinicalDevelopmentExpenses', window );">Clinical development expenses</a></td>
<td class="nump">$ 85,694<span></span>
</td>
<td class="nump">$ 116,460<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="Show.showAR( this, 'defref_ions_AccruedInLicensingFeesCurrent', window );">In-licensing expenses</a></td>
<td class="nump">12,704<span></span>
</td>
<td class="nump">7,945<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="Show.showAR( this, 'defref_ions_AccruedCommercialExpensesCurrent', window );">Commercial expenses</a></td>
<td class="nump">4,704<span></span>
</td>
<td class="nump">3,498<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_OtherAccruedLiabilitiesCurrent', window );">Other miscellaneous expenses</a></td>
<td class="nump">9,600<span></span>
</td>
<td class="nump">12,198<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AccruedLiabilitiesCurrent', window );">Total accrued liabilities</a></td>
<td class="nump">$ 112,702<span></span>
</td>
<td class="nump">$ 140,101<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_AccruedClinicalDevelopmentExpenses">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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 development 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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_AccruedClinicalDevelopmentExpenses</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_AccruedCommercialExpensesCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
</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_AccruedInLicensingFeesCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
</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_AccruedLiabilitiesCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_AccruedLiabilitiesCurrentAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
</tr>
<tr>
<td style="padding-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_OtherAccruedLiabilitiesCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherAccruedLiabilitiesCurrent</td>
</tr>
<tr>
<td style="padding-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>47
<FILENAME>R34.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="include/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;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686055775616">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements, Biogen (Details) - USD ($)<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="1"></th>
</tr>
<tr>
<th class="th"><div>Apr. 30, 2023</div></th>
<th class="th"><div>Mar. 31, 2023</div></th>
<th class="th"><div>Mar. 31, 2022</div></th>
<th class="th"><div>Dec. 31, 2022</div></th>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 130,524<span></span>
</td>
<td class="nump">$ 141,919<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="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">50,247<span></span>
</td>
<td class="nump">53,818<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="Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueMember', 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="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">62,756<span></span>
</td>
<td class="nump">69,634<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="Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationsMember', window );">Biogen 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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">70,501<span></span>
</td>
<td class="nump">$ 93,867<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 340,900<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 351,200<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationsMember', window );">Biogen Collaborations [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="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="Show.showAR( this, 'defref_us-gaap_ConcentrationRiskPercentage1', window );">Concentration percentage</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">54.00%<span></span>
</td>
<td class="nump">66.00%<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="Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationsMember', window );">Biogen Collaborations [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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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 custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 3,500,000<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="Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationsMember', window );">Biogen Collaborations [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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">50,247<span></span>
</td>
<td class="nump">$ 53,818<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="Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaborationsMember', window );">Biogen Collaborations [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="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="Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">20,254<span></span>
</td>
<td class="nump">$ 40,049<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="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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 custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_MilestonePaymentEarnedAndRecognizedAsRevenueAsServicesArePerformed', window );">Milestone payment earned</a></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="Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaboration2012NeurologyMember', window );">2012 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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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 custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_NextPaymentToBeAchieved', window );">Next payment to be achieved</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>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaboration2013StrategicNeurologyMember', window );">2013 Strategic Neurology [Member] | Maximum [Member] | Subsequent Event [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="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 custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_NextPaymentToBeAchieved', window );">Next payment to be achieved</a></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>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_BiogenCollaboration2013StrategicNeurologyMember', window );">2013 Strategic Neurology [Member] | Tofersen [Member] | Subsequent Event [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="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="Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">$ 16,000<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>
</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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_MilestonePaymentEarnedAndRecognizedAsRevenueAsServicesArePerformed">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Milestone payment earned during the period and recognized as revenue as services are performed.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_MilestonePaymentEarnedAndRecognizedAsRevenueAsServicesArePerformed</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_NextPaymentToBeAchieved">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The next payment to be achieved under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_NextPaymentToBeAchieved</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_ConcentrationRiskPercentage1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://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 https://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 https://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 https://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6404-108592<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
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</tr>
<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>
</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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126919976&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 https://asc.fasb.org/extlink&amp;oid=126920106&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 https://asc.fasb.org/extlink&amp;oid=126919976&amp;loc=SL49130532-203044<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126920106&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126920106&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 https://asc.fasb.org/extlink&amp;oid=6472922&amp;loc=d3e499488-122856<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_SpinrazaRoyaltiesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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>
</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_ResearchAndDevelopmentRevenueMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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_ResearchAndDevelopmentRevenueMember</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_BiogenCollaborationsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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_BiogenCollaboration2012NeurologyMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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_BiogenCollaboration2012NeurologyMember</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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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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<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>
</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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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>
<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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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_srt_ProductOrServiceAxis=ions_TofersenMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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_TofersenMember</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>
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<tr>
<td><strong> Period Type:</strong></td>
<td></td>
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140685987561920">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements, GSK (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="2">3 Months Ended</th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th"><div>Mar. 31, 2023</div></th>
<th class="th"><div>Mar. 31, 2022</div></th>
<th class="th"><div>Dec. 31, 2022</div></th>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">$ 130,524<span></span>
</td>
<td class="nump">$ 141,919<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="Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueMember', 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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">62,756<span></span>
</td>
<td class="nump">$ 69,634<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="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_NextPaymentToBeAchieved', window );">Next payment to be achieved</a></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="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="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="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ConcentrationRiskPercentage1', window );">Concentration percentage</a></td>
<td class="nump">11.00%<span></span>
</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="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></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="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">15,000<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="Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_GlaxoSmithKlineCollaborationMember', window );">GSK [Member] | Bepirovirsen [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="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">$ 15,000<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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_NextPaymentToBeAchieved">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The next payment to be achieved under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_NextPaymentToBeAchieved</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_ConcentrationRiskPercentage1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://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 https://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 https://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 https://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6404-108592<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126919976&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 https://asc.fasb.org/extlink&amp;oid=126920106&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 https://asc.fasb.org/extlink&amp;oid=126919976&amp;loc=SL49130532-203044<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126920106&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://asc.fasb.org/extlink&amp;oid=126920106&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 https://asc.fasb.org/extlink&amp;oid=6472922&amp;loc=d3e499488-122856<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_ResearchAndDevelopmentRevenueMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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_ResearchAndDevelopmentRevenueMember</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_GlaxoSmithKlineCollaborationMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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_GlaxoSmithKlineCollaborationMember</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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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>
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<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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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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<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>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_BepirovirsenMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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_BepirovirsenMember</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>
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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>
</tr>
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</TEXT>
</DOCUMENT>
<DOCUMENT>
<TYPE>XML
<SEQUENCE>49
<FILENAME>R36.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="include/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;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686055629728">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Basic and Diluted Net Loss Per Share (Details)<br></strong></div></th>
<th class="th"><div>Mar. 31, 2023</div></th>
<th class="th"><div>Dec. 31, 2022</div></th>
<th class="th"><div>Mar. 31, 2022</div></th>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_EarningsPerShareDilutedAbstract', window );"><strong>Diluted Net 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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_EarningsPerShareDilutedAbstract', window );"><strong>Diluted Net 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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</td>
<td class="nump">0.125%<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_DebtInstrumentInterestRateStatedPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
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<td>dtr-types:percentItemType</td>
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<td>na</td>
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<tr>
<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_us-gaap_EarningsPerShareDilutedAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
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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>
<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_ConvertibleSeniorNotes0PercentMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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>
</table>
<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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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>
</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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</div>
</body>
</html>
</TEXT>
</DOCUMENT>
<DOCUMENT>
<TYPE>XML
<SEQUENCE>50
<FILENAME>R37.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="include/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;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686059890064">
<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">3 Months Ended</th>
</tr>
<tr><th class="th"><div>Mar. 31, 2023</div></th></tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="Show.showAR( this, 'defref_ions_AvailableForSaleSecuritiesDebtMaturitiesWithinOneYearPercentage', window );">One year or less</a></td>
<td class="nump">74.00%<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="Show.showAR( this, 'defref_ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage', window );">After one year but within two years</a></td>
<td class="nump">23.00%<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="Show.showAR( this, 'defref_ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage', window );">After two years but within three and a half years</a></td>
<td class="nump">3.00%<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="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="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="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">97.00%<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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
</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>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>
</tr>
</table></div>
</div></td></tr>
</table>
<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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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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<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_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
</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_AvailableForSaleSecuritiesDebtMaturitiesWithinOneYearPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
</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_AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
</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_ions_MaximumContractMaturityPeriodRange1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
</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_MaximumContractMaturityPeriodRange2">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
</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>
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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_ions_MaximumContractMaturityPeriodRange3">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
</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>
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<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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
</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>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td>duration</td>
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<head>
<title></title>
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140685987386144">
<tr>
<th class="tl" colspan="2" rowspan="2"><div style="width: 200px;"><strong>Investments, Summary of Investments (Details)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th">
<div>Mar. 31, 2023 </div>
<div>USD ($) </div>
<div>Company</div>
</th>
<th class="th">
<div>Dec. 31, 2022 </div>
<div>USD ($)</div>
</th>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_InvestmentsAllOtherInvestmentsAbstract', window );"><strong>Ownership Interests in Private and Public Companies [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 custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment', window );">Number of private companies in which there is an equity ownership interest of less than 20% | Company</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">7<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="Show.showAR( this, 'defref_ions_NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment', window );">Number of public companies in which there is an equity ownership interest of less than 20% | Company</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">3<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesCurrentAbstract', window );"><strong>Available-for-sale Debt Securities with Maturity of One Year or Less [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="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleAmortizedCostCurrent', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 1,485,285<span></span>
</td>
<td class="nump">$ 1,223,522<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="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxCurrent', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">197<span></span>
</td>
<td class="nump">64<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="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(11,545)<span></span>
</td>
<td class="num">(12,018)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecuritiesCurrent', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,473,937<span></span>
</td>
<td class="nump">1,211,568<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesNoncurrentAbstract', window );"><strong>Available-for-sale Debt Securities with Maturity of More Than One Year [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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleAmortizedCostNoncurrent', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">572,511<span></span>
</td>
<td class="nump">525,314<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="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,062<span></span>
</td>
<td class="nump">130<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="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxNoncurrent', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(8,762)<span></span>
</td>
<td class="num">(15,621)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecuritiesNoncurrent', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">564,811<span></span>
</td>
<td class="nump">509,823<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Available-for-sale Debt Securities [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="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">2,057,796<span></span>
</td>
<td class="nump">1,748,836<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">1,259<span></span>
</td>
<td class="nump">194<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">(20,307)<span></span>
</td>
<td class="num">(27,639)<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">2,038,748<span></span>
</td>
<td class="nump">1,721,391<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFVNIAbstract', window );"><strong>Equity Securities [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="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">35,012<span></span>
</td>
<td class="nump">35,012<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="Show.showAR( this, 'defref_ions_EquitySecuritiesFvNiAccumulatedGrossUnrealizedGain', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">25,001<span></span>
</td>
<td class="nump">17,257<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="Show.showAR( this, 'defref_ions_EquitySecuritiesFvNiAccumulatedGrossUnrealizedLoss', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(9,633)<span></span>
</td>
<td class="num">(1,358)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">50,380<span></span>
</td>
<td class="nump">50,911<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_InvestmentsDebtAndEquitySecuritiesAbstract', window );"><strong>Available-for-sale Debt and Equity Securities [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="reu">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiCost', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">2,092,808<span></span>
</td>
<td class="nump">1,783,848<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="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">26,260<span></span>
</td>
<td class="nump">17,451<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="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">(29,940)<span></span>
</td>
<td class="num">(28,997)<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="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">2,089,128<span></span>
</td>
<td class="nump">1,772,302<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_CorporateDebtSecuritiesMember', window );">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="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesCurrentAbstract', window );"><strong>Available-for-sale Debt Securities with Maturity of One Year or Less [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="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleAmortizedCostCurrent', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="nump">623,940<span></span>
</td>
<td class="nump">513,790<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="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxCurrent', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">62<span></span>
</td>
<td class="nump">23<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="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(6,026)<span></span>
</td>
<td class="num">(4,365)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecuritiesCurrent', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">617,976<span></span>
</td>
<td class="nump">509,448<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesNoncurrentAbstract', window );"><strong>Available-for-sale Debt Securities with Maturity of More Than One Year [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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleAmortizedCostNoncurrent', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">200,661<span></span>
</td>
<td class="nump">227,631<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="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">336<span></span>
</td>
<td class="nump">14<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="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxNoncurrent', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(5,205)<span></span>
</td>
<td class="num">(10,143)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecuritiesNoncurrent', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">195,792<span></span>
</td>
<td class="nump">217,502<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_USGovernmentAgenciesDebtSecuritiesMember', window );">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="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesCurrentAbstract', window );"><strong>Available-for-sale Debt Securities with Maturity of One Year or Less [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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleAmortizedCostCurrent', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">247,629<span></span>
</td>
<td class="nump">133,585<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="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxCurrent', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">69<span></span>
</td>
<td class="nump">0<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="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(1,283)<span></span>
</td>
<td class="num">(1,829)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecuritiesCurrent', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">246,415<span></span>
</td>
<td class="nump">131,756<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesNoncurrentAbstract', window );"><strong>Available-for-sale Debt Securities with Maturity of More Than One Year [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="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleAmortizedCostNoncurrent', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">99,635<span></span>
</td>
<td class="nump">34,339<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="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">256<span></span>
</td>
<td class="nump">0<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="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxNoncurrent', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(649)<span></span>
</td>
<td class="num">(1,040)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecuritiesNoncurrent', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">99,242<span></span>
</td>
<td class="nump">33,299<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_USTreasurySecuritiesMember', window );">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="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesCurrentAbstract', window );"><strong>Available-for-sale Debt Securities with Maturity of One Year or Less [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="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleAmortizedCostCurrent', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="nump">556,394<span></span>
</td>
<td class="nump">512,655<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="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxCurrent', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">62<span></span>
</td>
<td class="nump">23<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="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(3,738)<span></span>
</td>
<td class="num">(5,124)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecuritiesCurrent', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">552,718<span></span>
</td>
<td class="nump">507,554<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesNoncurrentAbstract', window );"><strong>Available-for-sale Debt Securities with Maturity of More Than One Year [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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleAmortizedCostNoncurrent', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">257,651<span></span>
</td>
<td class="nump">245,030<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="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">364<span></span>
</td>
<td class="nump">0<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="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxNoncurrent', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(2,726)<span></span>
</td>
<td class="num">(4,109)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecuritiesNoncurrent', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">255,289<span></span>
</td>
<td class="nump">240,921<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesCurrentAbstract', window );"><strong>Available-for-sale Debt Securities with Maturity of One Year or Less [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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleAmortizedCostCurrent', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">57,322<span></span>
</td>
<td class="nump">57,484<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="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxCurrent', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">4<span></span>
</td>
<td class="nump">18<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="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(498)<span></span>
</td>
<td class="num">(686)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecuritiesCurrent', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">56,828<span></span>
</td>
<td class="nump">56,816<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesNoncurrentAbstract', window );"><strong>Available-for-sale Debt Securities with Maturity of More Than One Year [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="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleAmortizedCostNoncurrent', window );">Amortized cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">14,564<span></span>
</td>
<td class="nump">18,314<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="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">106<span></span>
</td>
<td class="nump">116<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="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxNoncurrent', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(182)<span></span>
</td>
<td class="num">(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="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecuritiesNoncurrent', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">14,488<span></span>
</td>
<td class="nump">18,101<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=us-gaap_OtherDebtSecuritiesMember', window );">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="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesCurrentAbstract', window );"><strong>Available-for-sale Debt Securities with Maturity of One Year or Less [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="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleAmortizedCostCurrent', 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">6,008<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="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxCurrent', 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="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent', 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">(14)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecuritiesCurrent', 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">5,994<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=ions_EquitySecuritiesPubliclyTradedCompaniesMember', window );">Publicly Traded 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="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFVNIAbstract', window );"><strong>Equity Securities [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="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">11,897<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="Show.showAR( this, 'defref_ions_EquitySecuritiesFvNiAccumulatedGrossUnrealizedGain', 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="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_EquitySecuritiesFvNiAccumulatedGrossUnrealizedLoss', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(4,508)<span></span>
</td>
<td class="num">(1,358)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">7,389<span></span>
</td>
<td class="nump">10,539<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_InvestmentsDebtAndEquitySecuritiesAbstract', window );"><strong>Available-for-sale Debt and Equity Securities [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="Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNiUnrealizedLoss', window );">Unrealized loss on equity securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(3,200)<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="Show.showAR( this, 'defref_us-gaap_FinancialInstrumentAxis=ions_EquitySecuritiesPrivateCompaniesMember', window );">Privately Held 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="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFVNIAbstract', window );"><strong>Equity Securities [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="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">23,115<span></span>
</td>
<td class="nump">23,115<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="Show.showAR( this, 'defref_ions_EquitySecuritiesFvNiAccumulatedGrossUnrealizedGain', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">25,001<span></span>
</td>
<td class="nump">17,257<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="Show.showAR( this, 'defref_ions_EquitySecuritiesFvNiAccumulatedGrossUnrealizedLoss', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(5,125)<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="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">42,991<span></span>
</td>
<td class="nump">$ 40,372<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_InvestmentsDebtAndEquitySecuritiesAbstract', window );"><strong>Available-for-sale Debt and Equity Securities [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="Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNiUnrealizedGain', window );">Unrealized gain on equity securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 2,600<span></span>
</td>
<td class="text">&#160;<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 in our condensed consolidated balance sheets.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[2]</td>
<td style="vertical-align: top;" valign="top">Our publicly traded equity securities are
            included in other current assets. We recognize publicly traded equity securities at fair value. In the three months ended&#160;March 31, 2023, we recognized a $3.2
            million unrealized loss in our condensed consolidated statements of operations related to a decrease in the fair value of our investments in publicly traded companies.</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-family: 'Times New Roman'; font-size: 10pt; color: #000000;">Our privately held equity securities are included in deposits and other assets. We recognize our privately held 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, which are Level 3 inputs<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">. In the three months ended March 31, 2023, we recorded a
              net gain of $</span>2.6<span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"> million in our condensed
              consolidated statements of operations related to changes in the fair value of our investments in privately held companies.</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_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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), classified as current.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxCurrent</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_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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), classified as noncurrent.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedGainBeforeTaxNoncurrent</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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), classified as current.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxCurrent</td>
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<td><strong> Balance Type:</strong></td>
<td>debit</td>
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<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_ions_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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), classified as noncurrent.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_DebtSecuritiesAvailableForSaleAccumulatedGrossUnrealizedLossBeforeTaxNoncurrent</td>
</tr>
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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>
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<td><strong> Balance Type:</strong></td>
<td>debit</td>
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<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
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<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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
</tr>
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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>
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<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_ions_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedGain">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
</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_DebtSecuritiesAvailableForSaleAndEquitySecuritiesFvNiGrossUnrealizedLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
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<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_EquitySecuritiesFvNiAccumulatedGrossUnrealizedGain">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Accumulated 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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_EquitySecuritiesFvNiAccumulatedGrossUnrealizedGain</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> Balance Type:</strong></td>
<td>credit</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_EquitySecuritiesFvNiAccumulatedGrossUnrealizedLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Accumulated 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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_EquitySecuritiesFvNiAccumulatedGrossUnrealizedLoss</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>instant</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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
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<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</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>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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126970911&amp;loc=d3e27161-111563<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126970911&amp;loc=d3e27161-111563<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126970911&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 https://asc.fasb.org/extlink&amp;oid=124258926&amp;loc=SL82898722-210454<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126897435&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 https://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 https://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 https://asc.fasb.org/extlink&amp;oid=126970911&amp;loc=d3e27161-111563<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
<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_AvailableForSaleSecuritiesDebtSecuritiesCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=124260329&amp;loc=d3e26626-111562<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_AvailableForSaleSecuritiesDebtSecuritiesNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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 noncurrent.</p></div>
<a href="javascript:void(0);" onclick="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 https://asc.fasb.org/extlink&amp;oid=124258926&amp;loc=SL82898722-210454<br><br>Reference 2: 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(12))<br> -URI https://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 320<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI https://asc.fasb.org/extlink&amp;oid=124260329&amp;loc=d3e26626-111562<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesDebtSecuritiesNoncurrent</td>
</tr>
<tr>
<td style="padding-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_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
</tr>
<tr>
<td style="padding-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_DebtSecuritiesAvailableForSaleAmortizedCostCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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), classified as current.</p></div>
<a href="javascript:void(0);" onclick="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 320<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI https://asc.fasb.org/extlink&amp;oid=126970911&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 https://asc.fasb.org/extlink&amp;oid=124258926&amp;loc=SL82898722-210454<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtSecuritiesAvailableForSaleAmortizedCostCurrent</td>
</tr>
<tr>
<td style="padding-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_DebtSecuritiesAvailableForSaleAmortizedCostNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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), classified as noncurrent.</p></div>
<a href="javascript:void(0);" onclick="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 https://asc.fasb.org/extlink&amp;oid=124258926&amp;loc=SL82898722-210454<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<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 https://asc.fasb.org/extlink&amp;oid=126970911&amp;loc=d3e27161-111563<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtSecuritiesAvailableForSaleAmortizedCostNoncurrent</td>
</tr>
<tr>
<td style="padding-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_DebtSecuritiesCurrentAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtSecuritiesCurrentAbstract</td>
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<td><strong> Balance Type:</strong></td>
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</table></div>
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</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtSecuritiesNoncurrentAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtSecuritiesNoncurrentAbstract</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>
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<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_EquitySecuritiesFVNIAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EquitySecuritiesFVNIAbstract</td>
</tr>
<tr>
<td 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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<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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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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(2))<br> -URI https://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 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -Subparagraph (f)<br> -URI https://asc.fasb.org/extlink&amp;oid=124098289&amp;loc=d3e6676-107765<br><br>Reference 3: 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 https://asc.fasb.org/extlink&amp;oid=123594786&amp;loc=SL75136599-209740<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
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<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
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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="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="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 https://asc.fasb.org/extlink&amp;oid=126980263&amp;loc=SL75117546-209714<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126980263&amp;loc=SL75117546-209714<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="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="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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<a href="javascript:void(0);" onclick="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 class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="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>
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686060137408">
<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>Mar. 31, 2023 </div>
<div>USD ($) </div>
<div>Investment</div>
</th>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesAbstract', window );"><strong>Temporarily Impaired Investments [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsNumberOfPositions', window );">Number of investments | Investment</a></td>
<td class="nump">603<span></span>
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<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionQualitativeDisclosureAbstract', window );"><strong>Estimated Fair Value [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12Months', window );">Less than 12 months of temporary impairment</a></td>
<td class="nump">$ 1,198,933<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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLonger', window );">More than 12 months of temporary impairment</a></td>
<td class="nump">486,918<span></span>
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<tr class="rou">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleUnrealizedLossPosition', window );">Total temporary impairment</a></td>
<td class="nump">1,685,851<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="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionAccumulatedLossAbstract', window );"><strong>Unrealized Losses [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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss', window );">Less than 12 months of temporary impairment</a></td>
<td class="num">(6,134)<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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLongerAccumulatedLoss', window );">More than 12 months of temporary impairment</a></td>
<td class="num">(14,173)<span></span>
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<tr class="rou">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleUnrealizedLossPositionAccumulatedLoss', window );">Total temporary impairment</a></td>
<td class="num">$ (20,307)<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="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="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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsNumberOfPositions', window );">Number of investments | Investment</a></td>
<td class="nump">361<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionQualitativeDisclosureAbstract', window );"><strong>Estimated Fair Value [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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12Months', window );">Less than 12 months of temporary impairment</a></td>
<td class="nump">$ 434,500<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLonger', window );">More than 12 months of temporary impairment</a></td>
<td class="nump">291,713<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleUnrealizedLossPosition', window );">Total temporary impairment</a></td>
<td class="nump">726,213<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionAccumulatedLossAbstract', window );"><strong>Unrealized Losses [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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss', window );">Less than 12 months of temporary impairment</a></td>
<td class="num">(1,697)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLongerAccumulatedLoss', window );">More than 12 months of temporary impairment</a></td>
<td class="num">(9,534)<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleUnrealizedLossPositionAccumulatedLoss', window );">Total temporary impairment</a></td>
<td class="num">$ (11,231)<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsNumberOfPositions', window );">Number of investments | Investment</a></td>
<td class="nump">68<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionQualitativeDisclosureAbstract', window );"><strong>Estimated Fair Value [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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12Months', window );">Less than 12 months of temporary impairment</a></td>
<td class="nump">$ 138,211<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLonger', window );">More than 12 months of temporary impairment</a></td>
<td class="nump">70,965<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleUnrealizedLossPosition', window );">Total temporary impairment</a></td>
<td class="nump">209,176<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionAccumulatedLossAbstract', window );"><strong>Unrealized Losses [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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss', window );">Less than 12 months of temporary impairment</a></td>
<td class="num">(424)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLongerAccumulatedLoss', window );">More than 12 months of temporary impairment</a></td>
<td class="num">(1,508)<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleUnrealizedLossPositionAccumulatedLoss', window );">Total temporary impairment</a></td>
<td class="num">$ (1,932)<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsNumberOfPositions', window );">Number of investments | Investment</a></td>
<td class="nump">64<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionQualitativeDisclosureAbstract', window );"><strong>Estimated Fair Value [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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12Months', window );">Less than 12 months of temporary impairment</a></td>
<td class="nump">$ 603,444<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLonger', window );">More than 12 months of temporary impairment</a></td>
<td class="nump">91,448<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleUnrealizedLossPosition', window );">Total temporary impairment</a></td>
<td class="nump">694,892<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionAccumulatedLossAbstract', window );"><strong>Unrealized Losses [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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss', window );">Less than 12 months of temporary impairment</a></td>
<td class="num">(3,873)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLongerAccumulatedLoss', window );">More than 12 months of temporary impairment</a></td>
<td class="num">(2,591)<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleUnrealizedLossPositionAccumulatedLoss', window );">Total temporary impairment</a></td>
<td class="num">$ (6,464)<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsNumberOfPositions', window );">Number of investments | Investment</a></td>
<td class="nump">110<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionQualitativeDisclosureAbstract', window );"><strong>Estimated Fair Value [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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12Months', window );">Less than 12 months of temporary impairment</a></td>
<td class="nump">$ 22,778<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLonger', window );">More than 12 months of temporary impairment</a></td>
<td class="nump">32,792<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleUnrealizedLossPosition', window );">Total temporary impairment</a></td>
<td class="nump">55,570<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionAccumulatedLossAbstract', window );"><strong>Unrealized Losses [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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss', window );">Less than 12 months of temporary impairment</a></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="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLongerAccumulatedLoss', window );">More than 12 months of temporary impairment</a></td>
<td class="num">(540)<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtSecuritiesAvailableForSaleUnrealizedLossPositionAccumulatedLoss', window );">Total temporary impairment</a></td>
<td class="num">$ (680)<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_AvailableForSaleSecuritiesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesAbstract</td>
</tr>
<tr>
<td style="padding-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>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionAccumulatedLossAbstract</td>
</tr>
<tr>
<td style="padding-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_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionQualitativeDisclosureAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionQualitativeDisclosureAbstract</td>
</tr>
<tr>
<td style="padding-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_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLonger">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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 more than 12 months, without allowance for credit loss. Includes beneficial interest in securitized financial asset.</p></div>
<a href="javascript:void(0);" onclick="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 https://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 https://asc.fasb.org/extlink&amp;oid=126970911&amp;loc=d3e27337-111563<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 https://asc.fasb.org/extlink&amp;oid=121590138&amp;loc=SL82922954-210456<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLonger</td>
</tr>
<tr>
<td style="padding-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_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLongerAccumulatedLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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 12 months or longer, without allowance for credit loss. Includes beneficial interest in securitized financial asset.</p></div>
<a href="javascript:void(0);" onclick="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 https://asc.fasb.org/extlink&amp;oid=126970911&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 https://asc.fasb.org/extlink&amp;oid=124269663&amp;loc=SL82922890-210455<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPosition12MonthsOrLongerAccumulatedLoss</td>
</tr>
<tr>
<td style="padding-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><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126970911&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 https://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 https://asc.fasb.org/extlink&amp;oid=121590138&amp;loc=SL82922954-210456<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=126970911&amp;loc=d3e27337-111563<br></p></div>
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<td style="white-space:nowrap;">us-gaap_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss</td>
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<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=124269663&amp;loc=SL82922888-210455<br></p></div>
<a href="javascript:void(0);" onclick="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_DebtSecuritiesAvailableForSaleContinuousUnrealizedLossPositionLessThan12MonthsNumberOfPositions</td>
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<a href="javascript:void(0);" onclick="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 unrealized loss position without allowance for credit loss.</p></div>
<a href="javascript:void(0);" onclick="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 6<br> -Subparagraph (a)(1)<br> -URI https://asc.fasb.org/extlink&amp;oid=126970911&amp;loc=d3e27290-111563<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 4<br> -Subparagraph (a)(1)<br> -URI https://asc.fasb.org/extlink&amp;oid=124269663&amp;loc=SL82922888-210455<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 https://asc.fasb.org/extlink&amp;oid=121590138&amp;loc=SL82922954-210456<br></p></div>
<a href="javascript:void(0);" onclick="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="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 unrealized loss position, without allowance for credit loss. Includes beneficial interest in securitized financial asset.</p></div>
<a href="javascript:void(0);" onclick="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 6<br> -Subparagraph (a)(2)<br> -URI https://asc.fasb.org/extlink&amp;oid=126970911&amp;loc=d3e27290-111563<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 4<br> -Subparagraph (a)(2)<br> -URI https://asc.fasb.org/extlink&amp;oid=124269663&amp;loc=SL82922888-210455<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<th class="tl" colspan="2" rowspan="1"><div style="width: 200px;"><strong>Fair Value Measurements (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="2"><div>Mar. 31, 2023</div></th>
<th class="th" colspan="2"><div>Dec. 31, 2022</div></th>
<th class="th"><div>Mar. 31, 2022</div></th>
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<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
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<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
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<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
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<td class="nump">$ 2,038,748<span></span>
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<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 1,721,391<span></span>
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<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
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<td class="nump">$ 50,380<span></span>
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<td class="nump">$ 50,911<span></span>
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<td class="fn" style="border-bottom: 0px;"></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="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>
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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>
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<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
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<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="nump">0.125%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0.125%<span></span>
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<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
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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>
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<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
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<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
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<td class="nump">0.00%<span></span>
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<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0.00%<span></span>
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<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0.00%<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>
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<td class="fn" style="border-bottom: 0px;"></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="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="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="Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNi', window );">Equity securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 7,389<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 10,539<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="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="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="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="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="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">276,352<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">211,655<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="Show.showAR( this, 'defref_us-gaap_AssetsFairValueDisclosure', window );">Total</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">2,322,489<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">1,943,585<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="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="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="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="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="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">813,768<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="nump">726,950<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="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="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="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="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="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="nump">11,000<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="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="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="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="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="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="nump">345,657<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">165,055<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="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="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="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="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="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="nump">808,007<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">748,475<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="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="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="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="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="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">71,316<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[4]</sup></td>
<td class="nump">74,917<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2]</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="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] | 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="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="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="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="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">1,000<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>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="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="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="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="Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">5,994<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="Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Publicly Traded Equity Securities [Member] | Other Current Assets [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="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="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="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="Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNi', window );">Equity securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[5]</sup></td>
<td class="nump">7,389<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">10,539<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="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="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="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="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="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">276,352<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">211,655<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="Show.showAR( this, 'defref_us-gaap_AssetsFairValueDisclosure', window );">Total</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,091,748<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">970,669<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="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="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="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="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="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="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="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="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="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="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="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="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="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="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="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="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="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">808,007<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">748,475<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="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="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="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="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="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="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="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="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="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="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="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="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="Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Publicly Traded Equity 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="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="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="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="Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNi', window );">Equity securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">7,389<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">10,539<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="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="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="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="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="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="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="Show.showAR( this, 'defref_us-gaap_AssetsFairValueDisclosure', window );">Total</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,230,741<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">972,916<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="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="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="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="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="Show.showAR( this, 'defref_us-gaap_NotesPayableFairValueDisclosure', window );">Convertible notes</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">506,300<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">498,900<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="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="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="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="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="Show.showAR( this, 'defref_us-gaap_NotesPayableFairValueDisclosure', window );">Convertible notes</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">578,400<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">587,300<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="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="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="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="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="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">813,768<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">726,950<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="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="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="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="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="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">345,657<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">165,055<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="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="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="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="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="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="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="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="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="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="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="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">71,316<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">74,917<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="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="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="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="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="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="nump">5,994<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="Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Publicly Traded Equity 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="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="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="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="Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNi', window );">Equity 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="nump">$ 0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr><td colspan="6"></td></tr>
<tr><td colspan="6"><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 in our
            condensed consolidated balance sheets.</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 short-term investments in our
            condensed consolidated balance sheets.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[3]</td>
<td style="vertical-align: top;" valign="top">$11.0 million was included in cash and cash equivalents in our condensed consolidated balance sheets, with the difference included in short-term investments in our condensed
            consolidated balance sheets.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[4]</td>
<td style="vertical-align: top;" valign="top">$1.0 million was included in cash and cash equivalents in our condensed consolidated balance sheets, with the difference included in short-term investments in our condensed
            consolidated balance sheets.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[5]</td>
<td style="vertical-align: top;" valign="top">Included in other current assets in our
            condensed consolidated balance sheets.</td>
</tr>
</table></td></tr>
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<div style="display: none;">
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<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126976982&amp;loc=d3e19207-110258<br></p></div>
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<tr>
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<a href="javascript:void(0);" onclick="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="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 https://asc.fasb.org/extlink&amp;oid=126897435&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 https://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 https://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 https://asc.fasb.org/extlink&amp;oid=126970911&amp;loc=d3e27161-111563<br></p></div>
<a href="javascript:void(0);" onclick="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="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="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="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="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="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="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(2))<br> -URI https://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 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -Subparagraph (f)<br> -URI https://asc.fasb.org/extlink&amp;oid=124098289&amp;loc=d3e6676-107765<br><br>Reference 3: 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 https://asc.fasb.org/extlink&amp;oid=123594786&amp;loc=SL75136599-209740<br></p></div>
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">- Definition</a><div><p>Fair value portion of notes payable.</p></div>
<a href="javascript:void(0);" onclick="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 https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
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<td><strong> Period Type:</strong></td>
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<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember</td>
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<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FinancialInstrumentAxis=us-gaap_CorporateDebtSecuritiesMember</td>
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<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FinancialInstrumentAxis=us-gaap_USGovernmentAgenciesDebtSecuritiesMember</td>
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<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FinancialInstrumentAxis=us-gaap_USTreasurySecuritiesMember</td>
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<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FinancialInstrumentAxis=us-gaap_USStatesAndPoliticalSubdivisionsMember</td>
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<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FinancialInstrumentAxis=us-gaap_OtherDebtSecuritiesMember</td>
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<td><strong> Name:</strong></td>
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<td style="white-space:nowrap;">us-gaap_FairValueByFairValueHierarchyLevelAxis=us-gaap_FairValueInputsLevel2Member</td>
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<DOCUMENT>
<TYPE>XML
<SEQUENCE>54
<FILENAME>R41.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
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<head>
<title></title>
<link rel="stylesheet" type="text/css" href="include/report.css">
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140685986043360">
<tr>
<th class="tl" colspan="2" rowspan="2"><div style="width: 200px;"><strong>Stock-based Compensation Expense (Details)<br> $ / shares in Units, $ in Thousands</strong></div></th>
<th class="th" colspan="2">3 Months Ended</th>
</tr>
<tr>
<th class="th">
<div>Mar. 31, 2023 </div>
<div>USD ($) </div>
<div>Period </div>
<div>$ / shares </div>
<div>shares</div>
</th>
<th class="th">
<div>Mar. 31, 2022 </div>
<div>USD ($) </div>
<div>$ / shares</div>
</th>
</tr>
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<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationAbstract', window );"><strong>Stock-based Compensation Expense [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 26,948<span></span>
</td>
<td class="nump">$ 26,236<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_IncomeStatementLocationAxis=us-gaap_CostOfSalesMember', window );">Cost of Sales [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="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationAbstract', window );"><strong>Stock-based Compensation Expense [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="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AllocatedShareBasedCompensationExpense', window );">Stock-based compensation expense</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">119<span></span>
</td>
<td class="nump">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="Show.showAR( this, 'defref_us-gaap_IncomeStatementLocationAxis=ions_ResearchDevelopmentAndPatentExpensesMember', window );">Research, Development and Patent Expense [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="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationAbstract', window );"><strong>Stock-based Compensation Expense [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="Show.showAR( this, 'defref_us-gaap_AllocatedShareBasedCompensationExpense', window );">Stock-based compensation expense</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">19,567<span></span>
</td>
<td class="nump">19,082<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_IncomeStatementLocationAxis=us-gaap_SellingGeneralAndAdministrativeExpensesMember', window );">Selling, General and Administrative Expense [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="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationAbstract', window );"><strong>Stock-based Compensation Expense [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="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AllocatedShareBasedCompensationExpense', window );">Stock-based compensation expense</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">7,262<span></span>
</td>
<td class="nump">$ 6,994<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_EmployeeStockOptionMember', window );">Stock Options [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="Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedAbstract', window );"><strong>Unrecognized Compensation Expense [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="Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedStockOptions', window );">Unrecognized compensation expense related to non-vested stock options</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 60,200<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1', window );">Weighted average period for recognition</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">1 year 4 months 24 days<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="Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_EmployeeStockOptionMember', window );">Stock Options [Member] | Employees [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="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsAndMethodologyAbstract', window );"><strong>Weighted-Average Assumptions [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="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRate', window );">Risk-free interest rate</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">3.60%<span></span>
</td>
<td class="nump">1.70%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate', window );">Dividend yield</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0.00%<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="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsWeightedAverageVolatilityRate', window );">Volatility</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">47.50%<span></span>
</td>
<td class="nump">55.20%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1', window );">Expected life</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="text">6 years 3 months 18 days<span></span>
</td>
<td class="text">6 years 3 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="Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=ions_ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member', window );">Stock Options Granted Prior to January 1, 2022 [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="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsAndMethodologyAbstract', window );"><strong>Weighted-Average Assumptions [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="Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod', window );">Award term</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">7 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="Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=ions_ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember', window );">Stock Options Granted on January 1, 2022 and Thereafter [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="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsAndMethodologyAbstract', window );"><strong>Weighted-Average Assumptions [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="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod', window );">Award term</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></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="Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_EmployeeStockMember', window );">ESPP [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="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsAndMethodologyAbstract', window );"><strong>Weighted-Average Assumptions [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="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRate', window );">Risk-free interest rate</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">5.20%<span></span>
</td>
<td class="nump">0.60%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate', window );">Dividend yield</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0.00%<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="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsWeightedAverageVolatilityRate', window );">Volatility</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">36.70%<span></span>
</td>
<td class="nump">50.20%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1', window );">Expected life</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">6 months<span></span>
</td>
<td class="text">6 months<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_RestrictedStockUnitsRSUMember', window );">RSUs [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="Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedAbstract', window );"><strong>Unrecognized Compensation Expense [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="Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedShareBasedAwardsOtherThanOptions', window );">Unrecognized compensation cost related to non-vested units</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 79,100<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="Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1', window );">Weighted average period for recognition</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">1 year 9 months 18 days<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="Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_RestrictedStockUnitsRSUMember', window );">RSUs [Member] | Board of Directors [Member] | Minimum [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="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAdditionalGeneralDisclosuresAbstract', window );"><strong>RSUs and PRSUs [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="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></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="Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_RestrictedStockUnitsRSUMember', window );">RSUs [Member] | Board of Directors [Member] | Maximum [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="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAdditionalGeneralDisclosuresAbstract', window );"><strong>RSUs and PRSUs [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="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></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="Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_RestrictedStockUnitsRSUMember', window );">RSUs [Member] | Employees [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="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAdditionalGeneralDisclosuresAbstract', window );"><strong>RSUs and PRSUs [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="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">4 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue', window );">Weighted-average grant date fair value (in dollars per share) | $ / shares</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 39.85<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="Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_PerformanceSharesMember', window );">PRSUs [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="Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedAbstract', window );"><strong>Unrecognized Compensation Expense [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="Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedShareBasedAwardsOtherThanOptions', window );">Unrecognized compensation cost related to non-vested units</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 9,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1', window );">Weighted average period for recognition</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">2 years 2 months 12 days<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="Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_PerformanceSharesMember', window );">PRSUs [Member] | Section 16 Officers [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="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAdditionalGeneralDisclosuresAbstract', window );"><strong>RSUs and PRSUs [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 custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods', window );">Number of performance periods | Period</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></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="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></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="Show.showAR( this, 'defref_ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfUnitsGuaranteedToVest', window );">Number of units guaranteed to vest (in shares) | shares</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></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="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue', window );">Weighted-average grant date fair value (in dollars per share) | $ / shares</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 58.99<span></span>
</td>
<td class="nump">$ 42.28<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_PerformanceSharesMember', window );">PRSUs [Member] | Section 16 Officers [Member] | Minimum [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="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAdditionalGeneralDisclosuresAbstract', window );"><strong>RSUs and PRSUs [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 custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest', window );">Percentage of units guaranteed to vest</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></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="Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_PerformanceSharesMember', window );">PRSUs [Member] | Section 16 Officers [Member] | Maximum [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="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAdditionalGeneralDisclosuresAbstract', window );"><strong>RSUs and PRSUs [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="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfUnitsGuaranteedToVest', window );">Percentage of units guaranteed to vest</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></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="Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_PerformanceSharesMember', window );">PRSUs [Member] | Section 16 Officers [Member] | One-Year Period [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="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAdditionalGeneralDisclosuresAbstract', window );"><strong>RSUs and PRSUs [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="Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage', window );">Vesting percentage</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">33.30%<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="Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_PerformanceSharesMember', window );">PRSUs [Member] | Section 16 Officers [Member] | Two-Year Period [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="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAdditionalGeneralDisclosuresAbstract', window );"><strong>RSUs and PRSUs [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="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage', window );">Vesting percentage</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">33.30%<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="Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_PerformanceSharesMember', window );">PRSUs [Member] | Section 16 Officers [Member] | Three-Year Period [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="Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAdditionalGeneralDisclosuresAbstract', window );"><strong>RSUs and PRSUs [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="Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage', window );">Vesting percentage</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">33.30%<span></span>
</td>
<td class="text">&#160;<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">In 2021, our Compensation Committee approved
            an amendment to the 2011 Equity Incentive Plan, or 2011 Plan, and the <span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;">2020 Equity Incentive Plan, or</span> 2020 Plan, that increased the contractual term of stock
            options granted under these plans from seven years to ten years for stock options granted on January 1, 2022 and thereafter. We determined that we are unable to rely on our historical exercise data as a basis for estimating the expected
            life of stock options granted to employees following this change because the contractual term changed and we have no other means to reasonably estimate future exercise behavior. We therefore used the simplified method for determining the
            expected life of stock options granted to employees in the three months ended&#160;March 31, 2023 and 2022. Under the simplified method, we calculate the expected term as the average of the time-to-vesting and the contractual life of the options. As we gain additional
            historical information, we will transition to calculating our expected term based on our historical exercise patterns.</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_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfPerformancePeriods">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
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<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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_AllocatedShareBasedCompensationExpense">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Amount of expense for award under share-based payment arrangement. Excludes amount capitalized.</p></div>
<a href="javascript:void(0);" onclick="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 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (h)(1)(i)<br> -URI https://asc.fasb.org/extlink&amp;oid=128089324&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AllocatedShareBasedCompensationExpense</td>
</tr>
<tr>
<td style="padding-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_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (i)<br> -URI https://asc.fasb.org/extlink&amp;oid=128089324&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (i)<br> -URI https://asc.fasb.org/extlink&amp;oid=128089324&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedStockOptions">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (i)<br> -URI https://asc.fasb.org/extlink&amp;oid=128089324&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_ShareBasedCompensationAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_ShareBasedCompensationArrangementByShareBasedPaymentAwardAdditionalGeneralDisclosuresAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAdditionalGeneralDisclosuresAbstract</td>
</tr>
<tr>
<td style="padding-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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(1)<br> -URI https://asc.fasb.org/extlink&amp;oid=128089324&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsAndMethodologyAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
</tr>
<tr>
<td style="padding-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_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (f)(2)(iii)<br> -URI https://asc.fasb.org/extlink&amp;oid=128089324&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
</tr>
<tr>
<td style="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_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (f)(2)(iv)<br> -URI https://asc.fasb.org/extlink&amp;oid=128089324&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
</tr>
<tr>
<td style="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_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsWeightedAverageVolatilityRate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (f)(2)(ii)<br> -URI https://asc.fasb.org/extlink&amp;oid=128089324&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
</tr>
<tr>
<td style="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_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (d)(1)<br> -URI https://asc.fasb.org/extlink&amp;oid=128089324&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(1)<br> -URI https://asc.fasb.org/extlink&amp;oid=128089324&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(2)<br> -URI https://asc.fasb.org/extlink&amp;oid=128089324&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (f)(2)(i)<br> -URI https://asc.fasb.org/extlink&amp;oid=128089324&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
</tr>
<tr>
<td style="padding-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_IncomeStatementLocationAxis=us-gaap_CostOfSalesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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_CostOfSalesMember</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_IncomeStatementLocationAxis=ions_ResearchDevelopmentAndPatentExpensesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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=ions_ResearchDevelopmentAndPatentExpensesMember</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_IncomeStatementLocationAxis=us-gaap_SellingGeneralAndAdministrativeExpensesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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>
</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_EmployeeStockOptionMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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>
</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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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_AwardTypeAxis=ions_ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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=ions_ShareBasedPaymentArrangementOptionsGrantedPriorToJanuary12022Member</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=ions_ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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=ions_ShareBasedPaymentArrangementOptionsGrantedOnJanuary12022AndThereafterMember</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_EmployeeStockMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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_EmployeeStockMember</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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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=ions_ShareBasedPaymentArrangementBoardOfDirectorMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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_srt_RangeAxis=srt_MinimumMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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>
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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>
<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_AwardTypeAxis=us-gaap_PerformanceSharesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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>
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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>
</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_GranteeStatusAxis=srt_ExecutiveOfficerMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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_ExecutiveOfficerMember</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>
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<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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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>
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<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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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>
<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>
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<DOCUMENT>
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<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="include/report.css">
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<body>
<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686063961488">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Income Taxes (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="2">3 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Mar. 31, 2023</div></th>
<th class="th"><div>Mar. 31, 2022</div></th>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_IncomeTaxDisclosureAbstract', window );"><strong>Income Taxes [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="Show.showAR( this, 'defref_us-gaap_IncomeTaxExpenseBenefit', window );">Income tax expense</a></td>
<td class="nump">$ 11,380<span></span>
</td>
<td class="nump">$ 1,094<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_IncomeTaxDisclosureAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
</tr>
<tr>
<td style="padding-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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://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 https://asc.fasb.org/extlink&amp;oid=126901519&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 https://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 https://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 https://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 https://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 https://asc.fasb.org/extlink&amp;oid=124431687&amp;loc=d3e22658-107794<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
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</table></div>
</div></td></tr>
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</div>
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<DOCUMENT>
<TYPE>XML
<SEQUENCE>56
<FILENAME>R43.htm
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<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="include/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;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686056489904">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Liability Related to Sale of Future Royalties (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="1">1 Months Ended</th>
<th class="th" colspan="2">3 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Jan. 31, 2023</div></th>
<th class="th"><div>Mar. 31, 2023</div></th>
<th class="th"><div>Mar. 31, 2022</div></th>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_RoyaltyRevenueMonetizationAbstract', window );"><strong>Royalty Revenue Monetization [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 custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties', window );">Transaction costs</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 10,434<span></span>
</td>
<td class="nump">$ 0<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="Show.showAR( this, 'defref_ions_ProceedsFromSaleOfFutureRoyalties', window );">Proceeds from sale of future royalties</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">500,000<span></span>
</td>
<td class="nump">0<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="Show.showAR( this, 'defref_ions_InterestExpenseRelatedToSaleOfFutureRoyalties', window );">Interest expense related to sale of future royalties</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">15,363<span></span>
</td>
<td class="nump">$ 0<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="Show.showAR( this, 'defref_ions_LiabilityRelatedToSaleOfFutureRoyaltiesNet', window );">Net liability related to sale of future royalties</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">505,081<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="Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_RoyaltyPurchaseAgreementMember', window );">Royalty Purchase 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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_RoyaltyRevenueMonetizationAbstract', window );"><strong>Royalty Revenue Monetization [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 custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_UpfrontRoyaltyPaymentReceived', window );">Upfront payment received</a></td>
<td class="nump">$ 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="Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForAdditionalMilestones', window );">Maximum amount of payments receivable for additional milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 625,000<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="Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateEffectivePercentage', window );">Effective interest rate</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">13.50%<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="Show.showAR( this, 'defref_ions_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties', window );">Transaction costs</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 10,400<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="Show.showAR( this, 'defref_ions_ProceedsFromSaleOfFutureRoyalties', window );">Proceeds from sale of future royalties</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">500,000<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="Show.showAR( this, 'defref_ions_InterestExpenseRelatedToSaleOfFutureRoyalties', window );">Interest expense related to sale of future royalties</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">15,363<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="Show.showAR( this, 'defref_ions_LiabilityRelatedToSaleOfFutureRoyaltiesGross', window );">Liability related to sale of future royalties as of</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">515,363<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DeferredFinanceCostsNet', window );">Net issuance costs related to sale of future royalties</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(10,282)<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="Show.showAR( this, 'defref_ions_LiabilityRelatedToSaleOfFutureRoyaltiesNet', window );">Net liability related to sale of future royalties</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">505,081<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="Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_RoyaltyPurchaseAgreementMember', window );">Royalty Purchase Agreement [Member] | SPINRAZA [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="Show.showAR( this, 'defref_ions_RoyaltyRevenueMonetizationAbstract', window );"><strong>Royalty Revenue Monetization [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 custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_MaximumAmountOfAnnualSalesOnWhichRoyaltyPaymentsArePaid', window );">Maximum amount of annual sales on which royalty payments are paid</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 1,500,000<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="Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_RoyaltyPurchaseAgreementMember', window );">Royalty Purchase Agreement [Member] | 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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_RoyaltyRevenueMonetizationAbstract', window );"><strong>Royalty Revenue Monetization [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 custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_PercentageOfRoyaltyPaymentsPaidOnAnnualSalesOfMedicine', window );">Percentage of royalty payments paid on annual sales of medicine</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">25.00%<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="Show.showAR( this, 'defref_ions_MaximumRoyaltyPaymentsMadeBeforeRoyaltyInterestRevertsBack', window );">Maximum royalty payments made before royalty interest reverts back</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 475,000<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="Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_RoyaltyPurchaseAgreementMember', window );">Royalty Purchase Agreement [Member] | 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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_RoyaltyRevenueMonetizationAbstract', window );"><strong>Royalty Revenue Monetization [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 custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_PercentageOfRoyaltyPaymentsPaidOnAnnualSalesOfMedicine', window );">Percentage of royalty payments paid on annual sales of medicine</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">45.00%<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="Show.showAR( this, 'defref_ions_MaximumRoyaltyPaymentsMadeBeforeRoyaltyInterestRevertsBack', window );">Maximum royalty payments made before royalty interest reverts back</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 550,000<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="Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_RoyaltyPurchaseAgreementMember', window );">Royalty Purchase Agreement [Member] | 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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_RoyaltyRevenueMonetizationAbstract', window );"><strong>Royalty Revenue Monetization [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 custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ions_PercentageOfRoyaltyPaymentsPaidOnAnnualSalesOfMedicine', window );">Percentage of royalty payments paid on annual sales of medicine</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">25.00%<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_InterestExpenseRelatedToSaleOfFutureRoyalties">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Amount of interest expense using the effective interest rate method related to the sale of future royalties.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_InterestExpenseRelatedToSaleOfFutureRoyalties</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_LiabilityRelatedToSaleOfFutureRoyaltiesGross">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Amount, before accumulated amortization, of the liability related to the sale of future royalties, pursuant to a royalty purchase agreement, that the Company is entitled to receive under collaboration agreements with Biogen and Novartis. The balance will be amortized over the estimated life of the arrangement using the effective interest rate method.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_LiabilityRelatedToSaleOfFutureRoyaltiesGross</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_LiabilityRelatedToSaleOfFutureRoyaltiesNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Amount, after accumulated amortization, of the unamortized liability related to the sale of future royalties, pursuant to a royalty purchase agreement, that the Company is entitled to receive under collaboration agreements with Biogen and Novartis. The balance will be amortized over the estimated life of the arrangement using the effective interest rate method.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_LiabilityRelatedToSaleOfFutureRoyaltiesNet</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_MaximumAmountOfAnnualSalesOnWhichRoyaltyPaymentsArePaid">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of annual sales on which royalty payments are paid under the royalty purchase agreement.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_MaximumAmountOfAnnualSalesOnWhichRoyaltyPaymentsArePaid</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_MaximumAmountOfPaymentsReceivableForAdditionalMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for additional milestones under the royalty purchase agreement.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_MaximumAmountOfPaymentsReceivableForAdditionalMilestones</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_MaximumRoyaltyPaymentsMadeBeforeRoyaltyInterestRevertsBack">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Maximum royalty payments under the royalty purchase agreement made before royalty interest reverts back to the Company.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_MaximumRoyaltyPaymentsMadeBeforeRoyaltyInterestRevertsBack</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_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The cash outflow paid to third parties for transaction costs in connection with a monetization transaction of future SPINRAZA and pelacarsen royalties the Company is entitled to under collaboration and licensing agreements.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties</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_PercentageOfRoyaltyPaymentsPaidOnAnnualSalesOfMedicine">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The percentage of royalty payments paid on annual sales of medicine.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_PercentageOfRoyaltyPaymentsPaidOnAnnualSalesOfMedicine</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_ProceedsFromSaleOfFutureRoyalties">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The cash inflow from the sale of future royalties under a royalty purchase agreement.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_ProceedsFromSaleOfFutureRoyalties</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_RoyaltyRevenueMonetizationAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_RoyaltyRevenueMonetizationAbstract</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_UpfrontRoyaltyPaymentReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The amount of upfront payments received during the period under the royalty purchase agreement.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_UpfrontRoyaltyPaymentReceived</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_DebtInstrumentInterestRateEffectivePercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://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 https://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 https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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_DeferredFinanceCostsNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1D<br> -Subparagraph (a)<br> -URI https://asc.fasb.org/extlink&amp;oid=123466505&amp;loc=SL123495340-112611<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 3<br> -URI https://asc.fasb.org/extlink&amp;oid=124435984&amp;loc=d3e28555-108399<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
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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><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_TypeOfArrangementAxis=ions_RoyaltyPurchaseAgreementMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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_RoyaltyPurchaseAgreementMember</td>
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<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>
</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_srt_ProductOrServiceAxis=ions_SpinrazaMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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_SpinrazaMember</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>
</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_srt_RangeAxis=srt_MinimumMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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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<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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<td><strong> Balance Type:</strong></td>
<td></td>
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<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_srt_RangeAxis=srt_MaximumMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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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<tr>
<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>
</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_srt_ProductOrServiceAxis=ions_PelacarsenMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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_PelacarsenMember</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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<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
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<TYPE>XML
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<FILENAME>R44.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
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<title></title>
<link rel="stylesheet" type="text/css" href="include/report.css">
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<span style="display: none;">v3.23.1</span><table class="report" border="0" cellspacing="2" id="idm140686056690160">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Convertible Debt (Details) - USD ($)<br> $ / shares in Units, shares in Millions, $ in Millions</strong></div></th>
<th class="th" colspan="2">1 Months Ended</th>
<th class="th" colspan="1">3 Months Ended</th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th"><div>Apr. 30, 2021</div></th>
<th class="th"><div>Dec. 31, 2019</div></th>
<th class="th"><div>Mar. 31, 2023</div></th>
<th class="th"><div>Dec. 31, 2022</div></th>
<th class="th"><div>Mar. 31, 2022</div></th>
</tr>
<tr class="rh">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_DebtInstrumentFaceAmount', window );">Face amount of offering</a></td>
<td class="nump">$ 632.5<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">$ 632.5<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="nump">$ 9.5<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">Apr. 30,  2026<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">0.00%<span></span>
</td>
<td class="nump">0.00%<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="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="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="nump">$ 57.84<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="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="nump">$ 76.39<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="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="nump">10.9<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="Show.showAR( this, 'defref_ions_CallSpread', window );">Cost of call spread</a></td>
<td class="nump">46.9<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="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_PaymentsForHedgeFinancingActivities', window );">Purchase of note hedges</a></td>
<td class="nump">136.7<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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOfWarrants', window );">Proceeds from issuance of warrants</a></td>
<td class="nump">89.8<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>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="nump">100.00%<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="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_us-gaap_RepaymentsOfConvertibleDebt', window );">Repurchase of convertible notes</a></td>
<td class="nump">$ 257.0<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="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">1.00%<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="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>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">$ 548.8<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="nump">$ 3.8<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">Dec. 31,  2024<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="nump">$ 83.28<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="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="nump">$ 123.38<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="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="nump">6.6<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="Show.showAR( this, 'defref_ions_CallSpread', window );">Cost of call spread</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 52.6<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="Show.showAR( this, 'defref_us-gaap_PaymentsForHedgeFinancingActivities', window );">Purchase of note hedges</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">108.7<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="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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">$ 56.1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="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="nump">100.00%<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_CallSpread">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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>
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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>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ 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_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=126734703&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 https://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 https://asc.fasb.org/extlink&amp;oid=126897435&amp;loc=d3e534808-122878<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://asc.fasb.org/extlink&amp;oid=123466505&amp;loc=SL123495323-112611<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://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 https://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 https://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 https://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 https://asc.fasb.org/extlink&amp;oid=123466577&amp;loc=SL123495735-112612<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="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="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 https://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 https://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 https://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 https://asc.fasb.org/extlink&amp;oid=120391452&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><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>
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Contractual interest rate for funds borrowed, under the debt agreement.</p></div>
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<a href="javascript:void(0);" onclick="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>
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<a href="javascript:void(0);" onclick="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>
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<a href="javascript:void(0);" onclick="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>
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<a href="javascript:void(0);" onclick="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>
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<a href="javascript:void(0);" onclick="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>
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&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;1.&#160; Organization and 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; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Organization and Business 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; font-family: 'Times New Roman'; font-size: 10pt;"&gt;We incorporated in California on January 10, 1989. In conjunction with our initial public offering, we reorganized as a Delaware corporation in April
    1991. We are a leader in the discovery and development of RNA-targeted 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'; 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'; font-size: 10pt;"&gt;We prepared the unaudited interim condensed consolidated financial statements for the three months ended&#160;March 31, 2023 and 2022 on the same basis as the audited financial statements for the year ended December 31, 2022. We included all normal recurring adjustments in the financial statements, which we considered necessary for a fair presentation of our financial position at such dates and our
    operating results and cash flows for those periods. Our operating results for the interim periods may not be indicative of what our operating results will be for the entire year. For more complete financial information, these financial statements, and
    notes thereto, should be read in conjunction with the audited financial statements for the year ended December 31, 2022 included in our Annual
    Report on Form 10-K filed with the Securities and Exchange Commission, or SEC.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;In our condensed consolidated financial statements, we included the accounts of Ionis Pharmaceuticals, Inc. and the consolidated
    results of our wholly owned subsidiary, Akcea Therapeutics, Inc. and its wholly owned subsidiaries (&#x201c;we&#x201d;, &#x201c;us&#x201d; or &#x201c;our&#x201d;).&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;We operate as a &lt;span style="-sec-ix-hidden:Fact_d751d8638e404708bbf18fb6bb90a9f5"&gt;single&lt;/span&gt;
    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_baf534ae803246ddb035eb980683637d"&gt;single&lt;/span&gt;
    operating segment.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt;We prepare our condensed consolidated financial statements in conformity
      with accounting principles generally accepted in the United States, or &lt;/span&gt;U.S., that require us to make estimates and assumptions that affect the amounts reported in our condensed consolidated financial statements and accompanying notes. Actual
    results could differ from our estimates.&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'; font-size: 10pt;"&gt;We prepared the unaudited interim condensed consolidated financial statements for the three months ended&#160;March 31, 2023 and 2022 on the same basis as the audited financial statements for the year ended December 31, 2022. We included all normal recurring adjustments in the financial statements, which we considered necessary for a fair presentation of our financial position at such dates and our
    operating results and cash flows for those periods. Our operating results for the interim periods may not be indicative of what our operating results will be for the entire year. For more complete financial information, these financial statements, and
    notes thereto, should be read in conjunction with the audited financial statements for the year ended December 31, 2022 included in our Annual
    Report on Form 10-K filed with the Securities and Exchange Commission, or SEC.&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'; font-size: 10pt;"&gt;In our condensed consolidated financial statements, we included the accounts of Ionis Pharmaceuticals, Inc. and the consolidated
    results of our wholly owned subsidiary, Akcea Therapeutics, Inc. and its wholly owned subsidiaries (&#x201c;we&#x201d;, &#x201c;us&#x201d; or &#x201c;our&#x201d;).&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'; font-size: 10pt;"&gt;We operate as a &lt;span style="-sec-ix-hidden:Fact_d751d8638e404708bbf18fb6bb90a9f5"&gt;single&lt;/span&gt;
    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_baf534ae803246ddb035eb980683637d"&gt;single&lt;/span&gt;
    operating segment.&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'; 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; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt;We prepare our condensed consolidated financial statements in conformity
      with accounting principles generally accepted in the United States, or &lt;/span&gt;U.S., that require us to make estimates and assumptions that affect the amounts reported in our condensed consolidated financial statements and accompanying notes. Actual
    results could differ from our estimates.&lt;/div&gt;
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&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;2.&#160; Significant Accounting Policies&lt;/div&gt;

&lt;div&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'; font-size: 10pt;"&gt;Our significant accounting policies have not changed substantially from those included in our Annual Report on Form 10-K for the year ended
    December 31, 2022, other than as discussed below.&lt;/div&gt;

&lt;div&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'; font-size: 10pt; font-weight: bold;"&gt;Liability Related to Sale of Future 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'; font-size: 10pt;"&gt;In January 2023, we entered into a royalty purchase agreement with Royalty Pharma Investments, or Royalty Pharma, to monetize a portion
    of our future SPINRAZA and pelacarsen royalties we are entitled to under our arrangements with Biogen and Novartis, respectively. Refer to Note 10, &lt;span style="font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"&gt;Liability Related to
      Sale of Future Royalties&lt;/span&gt;, for further details on the 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'; font-size: 10pt;"&gt;We record upfront payments and milestone payments we receive from the sale of future royalties as a liability, net of transaction costs.
    We record royalty payments made to Royalty Pharma as a reduction of the liability and amortize the transaction costs over the estimated life of the related royalty stream. We account for the associated interest expense under the effective interest rate
    method, while continuing to recognize the full amount of royalty revenue in the period in which the counterparty sells the related product and recognizes the related 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'; font-size: 10pt;"&gt;The liability related to the sale of future royalties, effective interest rate and the related interest expense are calculated using our
    current estimate of anticipated future royalty payments under the arrangement, which we periodically reassess based on internal projections and information from our partners who are responsible for commercializing the medicines. If there is a material
    change in our estimate, we will prospectively adjust the liability related to the sale of future royalties, effective interest rate and the related interest expense.&lt;/div&gt;

&lt;div style="text-align: left; font-family: Calibri; 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'; font-size: 10pt; font-weight: bold;"&gt;Recently Adopted 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'; font-size: 10pt;"&gt;We do not expect any recently issued accounting standards to have a material impact to our financial results.&lt;/div&gt;
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    <ions:LiabilityRelatedToSaleOfFutureRoyaltiesPolicyPolicyTextBlock
      contextRef="c20230101to20230331"
      id="Text_b7c5af4b1b0e4fc8bc20d418e5181ffc">
&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'; font-size: 10pt; font-weight: bold;"&gt;Liability Related to Sale of Future 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'; font-size: 10pt;"&gt;In January 2023, we entered into a royalty purchase agreement with Royalty Pharma Investments, or Royalty Pharma, to monetize a portion
    of our future SPINRAZA and pelacarsen royalties we are entitled to under our arrangements with Biogen and Novartis, respectively. Refer to Note 10, &lt;span style="font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"&gt;Liability Related to
      Sale of Future Royalties&lt;/span&gt;, for further details on the 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'; font-size: 10pt;"&gt;We record upfront payments and milestone payments we receive from the sale of future royalties as a liability, net of transaction costs.
    We record royalty payments made to Royalty Pharma as a reduction of the liability and amortize the transaction costs over the estimated life of the related royalty stream. We account for the associated interest expense under the effective interest rate
    method, while continuing to recognize the full amount of royalty revenue in the period in which the counterparty sells the related product and recognizes the related 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'; font-size: 10pt;"&gt;The liability related to the sale of future royalties, effective interest rate and the related interest expense are calculated using our
    current estimate of anticipated future royalty payments under the arrangement, which we periodically reassess based on internal projections and information from our partners who are responsible for commercializing the medicines. If there is a material
    change in our estimate, we will prospectively adjust the liability related to the sale of future royalties, effective interest rate and the related interest expense.&lt;/div&gt;
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      contextRef="c20230101to20230331"
      id="Text_77f04263f8fd40e2bb811ff95d88cebe">
&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'; font-size: 10pt; font-weight: bold;"&gt;Recently Adopted 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'; font-size: 10pt;"&gt;We do not expect any recently issued accounting standards to have a material impact to our financial results.&lt;/div&gt;
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&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;3. Supplemental Financial Data&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Inventories&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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', Times, serif; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" 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'; font-size: 10pt; font-weight: bold;"&gt;March 31, 2023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;December 31, 2022&lt;/div&gt;
        &lt;/td&gt;

    &lt;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; 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'; font-size: 10pt;"&gt;Raw materials:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; white-space: nowrap;" 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; white-space: nowrap;" 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 19.4pt; color: #000000; font-family: 'Times New Roman'; 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; 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'; font-size: 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'; font-size: 10pt;"&gt;17,356&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #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'; font-size: 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'; font-size: 10pt;"&gt;17,061&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -18pt; margin-left: 28.4pt; color: #000000; font-family: 'Times New Roman'; 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; 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'; font-size: 10pt;"&gt;2,786&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; 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'; font-size: 10pt;"&gt;2,699&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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman'; 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; 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'; font-size: 10pt;"&gt;20,142&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;19,760&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Work in process&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'; font-size: 10pt;"&gt;1,840&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;2,109&lt;/div&gt;
        &lt;/td&gt;

    &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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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; 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'; font-size: 10pt;"&gt;218&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; 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'; font-size: 10pt;"&gt;164&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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman'; 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; 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'; 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'; font-size: 10pt;"&gt;22,200&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; 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'; 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'; font-size: 10pt;"&gt;22,033&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: Calibri; 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'; 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: left; text-indent: 36pt; font-family: 'Times New Roman'; 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', Times, serif; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" 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'; font-size: 10pt; font-weight: bold;"&gt;March 31, 2023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;December 31, 2022&lt;/div&gt;
        &lt;/td&gt;

    &lt;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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Clinical development expenses&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'; font-size: 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'; font-size: 10pt;"&gt;85,694&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #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'; font-size: 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'; font-size: 10pt;"&gt;116,460&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;In-licensing expenses&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'; font-size: 10pt;"&gt;12,704&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;7,945&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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; 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; 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'; font-size: 10pt;"&gt;4,704&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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: 76%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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; 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'; font-size: 10pt;"&gt;9,600&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; 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'; font-size: 10pt;"&gt;12,198&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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman'; 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; 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'; 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'; font-size: 10pt;"&gt;112,702&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; 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'; 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'; font-size: 10pt;"&gt;140,101&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:SupplementalBalanceSheetDisclosuresTextBlock>
    <us-gaap:ScheduleOfInventoryCurrentTableTextBlock
      contextRef="c20230101to20230331"
      id="Text_8ca956cffe974ce9a840a246a97aa16c">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Inventories&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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', Times, serif; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" 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'; font-size: 10pt; font-weight: bold;"&gt;March 31, 2023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;December 31, 2022&lt;/div&gt;
        &lt;/td&gt;

    &lt;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; 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'; font-size: 10pt;"&gt;Raw materials:&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; white-space: nowrap;" 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; white-space: nowrap;" 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 19.4pt; color: #000000; font-family: 'Times New Roman'; 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; 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'; font-size: 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'; font-size: 10pt;"&gt;17,356&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #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'; font-size: 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'; font-size: 10pt;"&gt;17,061&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -18pt; margin-left: 28.4pt; color: #000000; font-family: 'Times New Roman'; 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; 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'; font-size: 10pt;"&gt;2,786&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; 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'; font-size: 10pt;"&gt;2,699&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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman'; 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; 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'; font-size: 10pt;"&gt;20,142&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;19,760&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Work in process&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'; font-size: 10pt;"&gt;1,840&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;2,109&lt;/div&gt;
        &lt;/td&gt;

    &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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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; 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'; font-size: 10pt;"&gt;218&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; 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'; font-size: 10pt;"&gt;164&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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman'; 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; 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'; 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'; font-size: 10pt;"&gt;22,200&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; 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'; 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'; font-size: 10pt;"&gt;22,033&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="c20230331_PublicUtilitiesInventoryAxis_ClinicalRawMaterialsMember"
      decimals="-3"
      id="Fact_3043726b7f0d40479abbe8c68900b93f"
      unitRef="U002">17356000</us-gaap:InventoryRawMaterials>
    <us-gaap:InventoryRawMaterials
      contextRef="c20221231_PublicUtilitiesInventoryAxis_ClinicalRawMaterialsMember"
      decimals="-3"
      id="Fact_6cec13c5f4334a1ba6216a6bc406747c"
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    <us-gaap:InventoryRawMaterials
      contextRef="c20230331_PublicUtilitiesInventoryAxis_CommercialRawMaterialsMember"
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      id="Fact_4a8280762bb1470eace824e402d6b623"
      unitRef="U002">2786000</us-gaap:InventoryRawMaterials>
    <us-gaap:InventoryRawMaterials
      contextRef="c20221231_PublicUtilitiesInventoryAxis_CommercialRawMaterialsMember"
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      id="Fact_cf1accaf2b004921b424e5cd65e40c1f"
      unitRef="U002">2699000</us-gaap:InventoryRawMaterials>
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      id="Fact_9975fb0b2fa74f9e8ab81ebad8fb2237"
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    <us-gaap:InventoryRawMaterials
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      id="Fact_e7c4b729eb5c4047a12ddaf1f657b647"
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    <us-gaap:InventoryWorkInProcess
      contextRef="c20221231"
      decimals="-3"
      id="Fact_182d548d120f4e1daae74044c3e1bbe5"
      unitRef="U002">2109000</us-gaap:InventoryWorkInProcess>
    <us-gaap:InventoryFinishedGoods
      contextRef="c20230331"
      decimals="-3"
      id="Fact_b21c128f10e14f89b4963ecd92676ea1"
      unitRef="U002">218000</us-gaap:InventoryFinishedGoods>
    <us-gaap:InventoryFinishedGoods
      contextRef="c20221231"
      decimals="-3"
      id="Fact_70a3a016ecb849cd9021230823cf224d"
      unitRef="U002">164000</us-gaap:InventoryFinishedGoods>
    <us-gaap:InventoryNet
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      id="Fact_6f6a7ebaae1b4d95ace7fcfcf1fba210"
      unitRef="U002">22200000</us-gaap:InventoryNet>
    <us-gaap:InventoryNet
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      id="Fact_3e4c02edf53745679ae7e698216e7837"
      unitRef="U002">22033000</us-gaap:InventoryNet>
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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; font-family: 'Times New Roman'; 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: left; text-indent: 36pt; font-family: 'Times New Roman'; 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', Times, serif; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; padding-bottom: 2px; white-space: nowrap;" 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'; font-size: 10pt; font-weight: bold;"&gt;March 31, 2023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;December 31, 2022&lt;/div&gt;
        &lt;/td&gt;

    &lt;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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Clinical development expenses&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'; font-size: 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'; font-size: 10pt;"&gt;85,694&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #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'; font-size: 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'; font-size: 10pt;"&gt;116,460&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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%; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;In-licensing expenses&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'; font-size: 10pt;"&gt;12,704&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;7,945&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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; 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; 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'; font-size: 10pt;"&gt;4,704&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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: 76%; padding-bottom: 2px; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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; 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'; font-size: 10pt;"&gt;9,600&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; 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'; font-size: 10pt;"&gt;12,198&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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: justify; margin-left: 28.45pt; color: #000000; font-family: 'Times New Roman'; 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; 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'; 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'; font-size: 10pt;"&gt;112,702&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; 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'; 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'; font-size: 10pt;"&gt;140,101&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:AccruedClinicalDevelopmentExpenses
      contextRef="c20230331"
      decimals="-3"
      id="Fact_9fa65e9eb4874e529d2b5a8558dbeefc"
      unitRef="U002">85694000</ions:AccruedClinicalDevelopmentExpenses>
    <ions:AccruedClinicalDevelopmentExpenses
      contextRef="c20221231"
      decimals="-3"
      id="Fact_e1554d35bd0e4c82aabac0d765ba6ddc"
      unitRef="U002">116460000</ions:AccruedClinicalDevelopmentExpenses>
    <ions:AccruedInLicensingFeesCurrent
      contextRef="c20230331"
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      id="Fact_c222f622055145968e8cd08ff3a569bd"
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      id="Fact_7076c86dd1604e5a826b9716b8c0ca6e"
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      id="Fact_74d1a19cf230440593ea60ac85e2acd3"
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    <ions:AccruedCommercialExpensesCurrent
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    <us-gaap:OtherAccruedLiabilitiesCurrent
      contextRef="c20230331"
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      id="Fact_9ed0b35c739e48bbb51027c4ea2073ae"
      unitRef="U002">9600000</us-gaap:OtherAccruedLiabilitiesCurrent>
    <us-gaap:OtherAccruedLiabilitiesCurrent
      contextRef="c20221231"
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      id="Fact_b95beacb8e88464e9674b3d0a46cdaf4"
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    <us-gaap:AccruedLiabilitiesCurrent
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    <us-gaap:AccruedLiabilitiesCurrent
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      unitRef="U002">140101000</us-gaap:AccruedLiabilitiesCurrent>
    <us-gaap:CollaborativeArrangementDisclosureTextBlock
      contextRef="c20230101to20230331"
      id="Text_14b80b76c9e44f8f9e33d88c2cae9115">
&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;4.&#160; Collaborative Arrangements and Licensing 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'; font-size: 11pt;"&gt;&lt;span style="font-family: 'Times New Roman'; font-size: 10pt;"&gt;Below, we have included our Biogen and GSK collaborations, which are our
      only collaborations with substantive changes during 2023 from those included in Part IV, Item 15, Note 7 of our audited financial statements
      included in our Annual Report on Form 10-K for the year ended December 31, 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic; font-weight: bold;"&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; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt;We have several strategic collaborations with Biogen focused on using
      antisense technology to advance the treatment of neurological disorders. We developed and licensed to Biogen SPINRAZA, our approved medicine to treat people with spinal muscular atrophy, or SMA. Under our 2013 strategic neurology collaboration,
      Biogen developed QALSODY (tofersen), our recently approved medicine to treat people with superoxide dismutase 1 amyotrophic lateral sclerosis, or SOD1-ALS. We and Biogen are currently developing numerous investigational medicines to treat
      neurodegenerative diseases under these collaborations, including medicines in development to treat people with &lt;/span&gt;amyotrophic lateral sclerosis, or ALS&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt;, SMA, Angelman
      Syndrome, Alzheimer&#x2019;s disease&lt;/span&gt;&lt;sub style="color: #000000;"&gt;&#160;&lt;/sub&gt;&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&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 &lt;/span&gt;March 31, 2023&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt;, we have received more than $&lt;/span&gt;3.5&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt; billion in payments from our Biogen collaborations.&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'; font-size: 10pt;"&gt;In the first quarter of 2023, we earned a $10
    million milestone payment from Biogen when we advanced ION582 under our 2012 neurology collaboration. We will recognize revenue as we perform services based on our effort to satisfy our research and development, or R&amp;amp;D, services performance
    obligation relative to the total effort expected to satisfy our performance obligation for ION582. We will achieve the next payment of up to $25
    million if Biogen advances another medicine under our 2012 neurology 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'; font-size: 10pt;"&gt;During the three months ended March 31, 2023 and 2022, we earned the following revenue from our relationship with Biogen (in thousands, 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', Times, serif; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Three Months Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;March 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;2023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;"&gt;2022&lt;/div&gt;
        &lt;/td&gt;

    &lt;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: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;50,247&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;53,818&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;20,254&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'; font-size: 10pt;"&gt;40,049&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: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;70,501&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;93,867&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;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'; 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'; font-size: 10pt;"&gt;66&lt;/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'; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: Calibri; 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'; font-size: 10pt;"&gt;In April 2023, we earned a $16 million
    milestone payment from Biogen when the FDA approved Biogen&#x2019;s New Drug Application, or NDA, for QALSODY. We will achieve the next payment of up to $20
    million if Biogen advances a medicine under the 2013 strategic neurology 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'; font-size: 10pt;"&gt;Our condensed consolidated balance sheets at March 31, 2023 and December 31, 2022&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt;&#160;&lt;/span&gt;included
    deferred revenue of $340.9 million and $351.2
    million, respectively, from our relationship with 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'; font-size: 10pt; font-style: italic; font-weight: bold;"&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; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt;In March 2010, we entered into a collaboration 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. Our collaboration with GSK currently includes bepirovirsen,
      our medicine in development targeting hepatitis B virus, or HBV. We designed this medicine 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;/span&gt;. From inception through March 31, 2023, we have received more than $105 million in an upfront payment and payments related to 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'; font-size: 10pt;"&gt;In the first quarter of 2023, we earned a $15
    million milestone payment when GSK initiated a Phase 3 program of bepirovirsen. We recognized this milestone payment as R&amp;amp;D revenue in full in the first quarter of 2023 because we did not have any remaining performance obligations related to the
    milestone payment. We will achieve the next payment of $15 million if the FDA accepts an NDA filing of bepirovirsen for review.&lt;/div&gt;

&lt;div&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'; font-size: 10pt;"&gt;During the three months ended March 31, 2023 and 2022, we earned the following revenue from our relationship with GSK (in thousands, 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', Times, serif; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Three Months Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;March 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;2023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;"&gt;2022&lt;/div&gt;
        &lt;/td&gt;

    &lt;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: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;15,000&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;11&lt;/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'; 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'; 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;/table&gt;

&lt;div style="text-align: left; font-family: Calibri; 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'; font-size: 10pt;"&gt;We did not have any
    deferred revenue from our relationship with GSK at March 31, 2023 or December 31, 2022.&lt;/div&gt;
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&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;During the three months ended March 31, 2023 and 2022, we earned the following revenue from our relationship with Biogen (in thousands, 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', Times, serif; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Three Months Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;March 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;2023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;"&gt;2022&lt;/div&gt;
        &lt;/td&gt;

    &lt;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: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;50,247&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;53,818&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;20,254&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'; font-size: 10pt;"&gt;40,049&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: left; text-indent: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;70,501&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;93,867&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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: -9pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;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'; 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'; font-size: 10pt;"&gt;66&lt;/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'; font-size: 10pt;"&gt;%&lt;/div&gt;
        &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: left; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;"&gt;During the three months ended March 31, 2023 and 2022, we earned the following revenue from our relationship with GSK (in thousands, 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', Times, serif; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Three Months Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;March 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;2023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;"&gt;2022&lt;/div&gt;
        &lt;/td&gt;

    &lt;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: -27pt; margin-left: 27pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;15,000&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;11&lt;/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'; 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'; 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;/table&gt;
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&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;5. Basic and Diluted Net 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'; font-size: 10pt; font-weight: bold;"&gt;Basic net 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'; font-size: 10pt;"&gt;We calculated our basic net loss per share for the three months ended&#160;March 31, 2023 and 2022 by dividing our net loss by our weighted-average number of common shares outstanding during the 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Diluted net 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'; font-size: 10pt;"&gt;For the three months ended&#160;March 31, 2023 and 2022, 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 from 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', Times, serif; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;0 percent convertible senior notes, or 0% Notes;&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', Times, serif; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Note hedges related to the 0% Notes;&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', Times, serif; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;0.125 percent convertible senior notes, or 0.125% Notes;&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', Times, serif; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Note hedges related to the 0.125% Notes;&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', Times, serif; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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', Times, serif; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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', Times, serif; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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', Times, serif; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Additionally as of March 31, 2023, we had
    warrants related to our 0% and 0.125%
    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;
</us-gaap:EarningsPerShareTextBlock>
    <us-gaap:EarningsPerSharePolicyTextBlock
      contextRef="c20230101to20230331"
      id="Text_9471c38bb7ae4e1287d0671ecea462a6">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Basic net 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'; font-size: 10pt;"&gt;We calculated our basic net loss per share for the three months ended&#160;March 31, 2023 and 2022 by dividing our net loss by our weighted-average number of common shares outstanding during the 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Diluted net 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'; font-size: 10pt;"&gt;For the three months ended&#160;March 31, 2023 and 2022, 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 from 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', Times, serif; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;0 percent convertible senior notes, or 0% Notes;&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', Times, serif; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Note hedges related to the 0% Notes;&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', Times, serif; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;0.125 percent convertible senior notes, or 0.125% Notes;&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', Times, serif; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Note hedges related to the 0.125% Notes;&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', Times, serif; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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', Times, serif; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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', Times, serif; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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', Times, serif; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&#x25cf;&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Additionally as of March 31, 2023, we had
    warrants related to our 0% and 0.125%
    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;
</us-gaap:EarningsPerSharePolicyTextBlock>
    <us-gaap:DebtInstrumentInterestRateStatedPercentage
      contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember"
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      unitRef="U003">0</us-gaap:DebtInstrumentInterestRateStatedPercentage>
    <us-gaap:DebtInstrumentInterestRateStatedPercentage
      contextRef="c20220331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember"
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      contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember"
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      contextRef="c20220331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember"
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      id="Fact_0ea297d0210a42d9a665d5dda26140b2"
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      contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember"
      decimals="2"
      id="Fact_cbe2bcc4c3d14b47bcbdeabac6ac057d"
      unitRef="U003">0</us-gaap:DebtInstrumentInterestRateStatedPercentage>
    <us-gaap:DebtInstrumentInterestRateStatedPercentage
      contextRef="c20220331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember"
      decimals="2"
      id="Fact_b7898ddbacfc4ae1946b18f1568fd7cf"
      unitRef="U003">0</us-gaap:DebtInstrumentInterestRateStatedPercentage>
    <us-gaap:DebtInstrumentInterestRateStatedPercentage
      contextRef="c20220331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember"
      decimals="5"
      id="Fact_e41939393b224ee783597306dc36daac"
      unitRef="U003">0.00125</us-gaap:DebtInstrumentInterestRateStatedPercentage>
    <us-gaap:DebtInstrumentInterestRateStatedPercentage
      contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember"
      decimals="5"
      id="Fact_c5e88dec0bd1430ca7e7d1de977b5a01"
      unitRef="U003">0.00125</us-gaap:DebtInstrumentInterestRateStatedPercentage>
    <us-gaap:DebtInstrumentInterestRateStatedPercentage
      contextRef="c20220331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember"
      decimals="5"
      id="Fact_a933b4f7afa1473d9df0d94a8d4afeb2"
      unitRef="U003">0.00125</us-gaap:DebtInstrumentInterestRateStatedPercentage>
    <us-gaap:DebtInstrumentInterestRateStatedPercentage
      contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember"
      decimals="5"
      id="Fact_5fde4c84acc044728945d893da112927"
      unitRef="U003">0.00125</us-gaap:DebtInstrumentInterestRateStatedPercentage>
    <us-gaap:DebtInstrumentInterestRateStatedPercentage
      contextRef="c20220331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember"
      decimals="5"
      id="Fact_a93777dfde714e38820482b10cce8665"
      unitRef="U003">0.00125</us-gaap:DebtInstrumentInterestRateStatedPercentage>
    <us-gaap:DebtInstrumentInterestRateStatedPercentage
      contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember"
      decimals="5"
      id="Fact_2ace2f3096e942c4bf2967102938f98f"
      unitRef="U003">0.00125</us-gaap:DebtInstrumentInterestRateStatedPercentage>
    <us-gaap:DebtInstrumentInterestRateStatedPercentage
      contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0PercentMember"
      decimals="2"
      id="Fact_79673f01eb3f4d0f8cc2a2ee82ba16a8"
      unitRef="U003">0</us-gaap:DebtInstrumentInterestRateStatedPercentage>
    <us-gaap:DebtInstrumentInterestRateStatedPercentage
      contextRef="c20230331_DebtInstrumentAxis_ConvertibleSeniorNotes0125PercentMember"
      decimals="5"
      id="Fact_8b9684e867694bc788bcce48cf27b9cb"
      unitRef="U003">0.00125</us-gaap:DebtInstrumentInterestRateStatedPercentage>
    <us-gaap:InvestmentTextBlock
      contextRef="c20230101to20230331"
      id="Text_b6e1a67fcacc41d1be3b24f234df60ad">
&lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;6.&#160; 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'; font-size: 10pt;"&gt;The following table summarizes the contract maturity of the available-for-sale securities we held as of March 31, 2023:&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', Times, serif; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;74&lt;/div&gt;
        &lt;/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'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;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'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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_f12cc57cfa544d218ac6c26f9aae5797"&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'; font-size: 10pt;"&gt;3&lt;/div&gt;
        &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'; 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;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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;&#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'; font-size: 10pt;"&gt;100&lt;/div&gt;
        &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'; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: Calibri; 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'; font-size: 10pt;"&gt;As illustrated above, at March 31, 2023,
    97 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'; font-size: 10pt;"&gt;All of our available-for-sale debt 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; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt;We invest in available-for-sale securities&lt;/span&gt; with strong credit
    ratings and an investment grade rating at or above A-1, P-1 or F-1 by Standard &amp;amp; Poor&#x2019;s, Moody&#x2019;s or Fitch, 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'; font-size: 10pt;"&gt;At March 31, 2023, we had
    an equity ownership interest of less than 20 percent in seven private companies and three public companies with which we conduct business.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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', Times, serif; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold; text-indent: 6.5pt;"&gt;Amortized&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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="6" 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'; 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;" 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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; 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'; font-size: 10pt; font-weight: bold;"&gt;&lt;span style="text-indent: 0pt;"&gt;March 31, 2023&lt;/span&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="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'; 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;" 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'; 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;" 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'; 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;" 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'; 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'; font-size: 10pt;"&gt;&lt;span style="text-decoration: underline;"&gt;Available-for-sale debt securities:&lt;/span&gt;&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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;623,940&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;62&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(6,026&lt;/div&gt;
        &lt;/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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;617,976&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;247,629&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;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;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(1,283&lt;/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'; 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'; font-size: 10pt;"&gt;246,415&lt;/div&gt;
        &lt;/td&gt;

    &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'; 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'; font-size: 10pt;"&gt;556,394&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;62&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(3,738&lt;/div&gt;
        &lt;/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'; 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'; font-size: 10pt;"&gt;552,718&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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 style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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;" valign="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'; font-size: 10pt;"&gt;57,322&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'; font-size: 10pt;"&gt;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;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'; font-size: 10pt;"&gt;(498&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'; 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'; font-size: 10pt;"&gt;56,828&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: 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'; font-size: 10pt;"&gt;Total debt 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'; font-size: 10pt;"&gt;1,485,285&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'; font-size: 10pt;"&gt;197&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'; font-size: 10pt;"&gt;(11,545&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'; 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'; font-size: 10pt;"&gt;1,473,937&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%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Corporate debt 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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;200,661&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;336&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;(5,205&lt;/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'; 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'; font-size: 10pt;"&gt;195,792&lt;/div&gt;
        &lt;/td&gt;

    &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'; 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'; font-size: 10pt;"&gt;99,635&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;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;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(649&lt;/div&gt;
        &lt;/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'; 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'; font-size: 10pt;"&gt;99,242&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;257,651&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;364&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;(2,726&lt;/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'; 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'; font-size: 10pt;"&gt;255,289&lt;/div&gt;
        &lt;/td&gt;

    &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%; 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'; 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: #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'; font-size: 10pt;"&gt;14,564&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'; font-size: 10pt;"&gt;106&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'; font-size: 10pt;"&gt;(182&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'; 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'; font-size: 10pt;"&gt;14,488&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;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Total debt 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;" valign="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'; font-size: 10pt;"&gt;572,511&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'; font-size: 10pt;"&gt;1,062&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'; font-size: 10pt;"&gt;(8,762&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'; 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'; font-size: 10pt;"&gt;564,811&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: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 27pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Total available-for-sale 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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;2,057,796&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'; 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'; font-size: 10pt;"&gt;1,259&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'; 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'; font-size: 10pt;"&gt;(20,307&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'; 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'; 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'; font-size: 10pt;"&gt;2,038,748&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%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&lt;span style="text-decoration: underline;"&gt;Equity securities:&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;&#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;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 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: 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'; font-size: 10pt;"&gt;Publicly traded 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(4,508&lt;/div&gt;
        &lt;/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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;7,389&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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 style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Privately held 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;" valign="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'; font-size: 10pt;"&gt;23,115&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'; font-size: 10pt;"&gt;25,001&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'; font-size: 10pt;"&gt;(5,125&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'; 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'; font-size: 10pt;"&gt;42,991&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: 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'; 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;&#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'; font-size: 10pt;"&gt;35,012&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'; font-size: 10pt;"&gt;25,001&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'; font-size: 10pt;"&gt;(9,633&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'; 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'; font-size: 10pt;"&gt;50,380&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;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 27pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Total available-for-sale debt and equity 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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;2,092,808&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'; 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'; font-size: 10pt;"&gt;26,260&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'; 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'; font-size: 10pt;"&gt;(29,940&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'; 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'; 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'; font-size: 10pt;"&gt;2,089,128&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="cfttable" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold; text-indent: 6.5pt;"&gt;Amortized&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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="6" 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'; 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;" 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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; 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'; font-size: 10pt; font-weight: bold;"&gt;&lt;span style="text-indent: 0pt;"&gt;December 31, 2022&lt;/span&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="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'; 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;" 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'; 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;" 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'; 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;" 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'; 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'; font-size: 10pt;"&gt;&lt;span style="text-decoration: underline;"&gt;Available-for-sale debt securities:&lt;/span&gt;&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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;513,790&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;23&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(4,365&lt;/div&gt;
        &lt;/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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;509,448&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;133,585&lt;/div&gt;
        &lt;/td&gt;

    &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'; 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'; font-size: 10pt;"&gt;(1,829&lt;/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'; 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'; font-size: 10pt;"&gt;131,756&lt;/div&gt;
        &lt;/td&gt;

    &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'; 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'; font-size: 10pt;"&gt;512,655&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;23&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(5,124&lt;/div&gt;
        &lt;/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'; 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'; font-size: 10pt;"&gt;507,554&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;57,484&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;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;&#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'; font-size: 10pt;"&gt;(686&lt;/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'; 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'; font-size: 10pt;"&gt;56,816&lt;/div&gt;
        &lt;/td&gt;

    &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%; 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'; 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'; font-size: 10pt;"&gt;6,008&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;&#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'; 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'; font-size: 10pt;"&gt;(14&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'; 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'; font-size: 10pt;"&gt;5,994&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;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Total debt 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;" valign="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'; font-size: 10pt;"&gt;1,223,522&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'; font-size: 10pt;"&gt;64&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'; font-size: 10pt;"&gt;(12,018&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'; 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'; font-size: 10pt;"&gt;1,211,568&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%; 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'; 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'; font-size: 10pt;"&gt;227,631&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;14&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(10,143&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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;217,502&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;34,339&lt;/div&gt;
        &lt;/td&gt;

    &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'; 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'; font-size: 10pt;"&gt;(1,040&lt;/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'; 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'; font-size: 10pt;"&gt;33,299&lt;/div&gt;
        &lt;/td&gt;

    &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'; 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'; font-size: 10pt;"&gt;245,030&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;(4,109&lt;/div&gt;
        &lt;/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'; 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'; font-size: 10pt;"&gt;240,921&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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 style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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;" valign="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'; font-size: 10pt;"&gt;18,314&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'; font-size: 10pt;"&gt;116&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'; font-size: 10pt;"&gt;(329&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'; 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'; font-size: 10pt;"&gt;18,101&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: 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'; font-size: 10pt;"&gt;Total debt 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'; font-size: 10pt;"&gt;525,314&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'; font-size: 10pt;"&gt;130&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'; font-size: 10pt;"&gt;(15,621&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'; 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'; font-size: 10pt;"&gt;509,823&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;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 27pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Total available-for-sale debt securities&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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;1,748,836&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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;194&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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(27,639&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'; 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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;1,721,391&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%; 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'; font-size: 10pt;"&gt;&lt;span style="text-decoration: underline;"&gt;Equity securities:&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;&#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%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Publicly traded equity securities included in other current assets (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'; 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'; 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%; 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'; 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'; 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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;(1,358&lt;/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'; 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'; 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'; font-size: 10pt;"&gt;10,539&lt;/div&gt;
        &lt;/td&gt;

    &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%; 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'; font-size: 10pt;"&gt;Privately held 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'; font-size: 10pt;"&gt;23,115&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'; font-size: 10pt;"&gt;17,257&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'; 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'; font-size: 10pt;"&gt;40,372&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;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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;" valign="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'; font-size: 10pt;"&gt;35,012&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'; font-size: 10pt;"&gt;17,257&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'; font-size: 10pt;"&gt;(1,358&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'; 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'; font-size: 10pt;"&gt;50,911&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: left; text-indent: 27pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Total available-for-sale debt 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'; 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'; font-size: 10pt;"&gt;1,783,848&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'; 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'; font-size: 10pt;"&gt;17,451&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'; 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'; font-size: 10pt;"&gt;(28,997&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'; 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'; 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'; font-size: 10pt;"&gt;1,772,302&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="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;Includes investments classified as cash
            equivalents in our condensed consolidated balance sheets.&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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;Our publicly traded equity securities are
            included in other current assets. We recognize publicly traded equity securities at fair value. In the three months ended&#160;March 31, 2023, we recognized a $3.2
            million unrealized loss in our condensed consolidated statements of operations related to a decrease in the fair value of our investments in publicly traded companies.&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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt;Our privately held equity securities are included in deposits and other assets. We recognize our privately held 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, which are Level 3 inputs&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt;. In the three months ended March 31, 2023, we recorded a
              net gain of $&lt;/span&gt;2.6&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt; million in our condensed
              consolidated statements of operations related to changes in the fair value of our investments in privately held companies.&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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;The following is a summary of our investments we consider to be temporarily impaired at March 31, 2023 (in thousands, except for number of investments):&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', Times, serif; 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; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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="6" 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'; font-size: 10pt; font-weight: bold;"&gt;Less than 12 Months of&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Temporary Impairment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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="6" 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'; font-size: 10pt; font-weight: bold;"&gt;More than 12 Months of&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Temporary Impairment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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="6" 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'; font-size: 10pt; font-weight: bold;"&gt;Total Temporary&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Impairment&lt;/div&gt;
        &lt;/td&gt;

    &lt;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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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'; 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;" 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'; font-size: 10pt; font-weight: bold;"&gt;Estimated&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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;" 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'; font-size: 10pt; font-weight: bold;"&gt;Unrealized&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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;" 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'; font-size: 10pt; font-weight: bold;"&gt;Estimated&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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;" 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'; font-size: 10pt; font-weight: bold;"&gt;Unrealized&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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;" 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'; font-size: 10pt; font-weight: bold;"&gt;Estimated&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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;" 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'; font-size: 10pt; font-weight: bold;"&gt;Unrealized&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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: 16%; 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'; 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'; font-size: 10pt;"&gt;361&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;434,500&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(1,697&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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;291,713&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(9,534&lt;/div&gt;
        &lt;/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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;726,213&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(11,231&lt;/div&gt;
        &lt;/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'; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 16%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;68&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;138,211&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;(424&lt;/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'; 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'; font-size: 10pt;"&gt;70,965&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;(1,508&lt;/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'; 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'; font-size: 10pt;"&gt;209,176&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;(1,932&lt;/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'; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 16%; 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'; 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'; 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;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;603,444&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(3,873&lt;/div&gt;
        &lt;/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'; 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'; font-size: 10pt;"&gt;91,448&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(2,591&lt;/div&gt;
        &lt;/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'; 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'; font-size: 10pt;"&gt;694,892&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(6,464&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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 16%; 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'; 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;" valign="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'; font-size: 10pt;"&gt;110&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'; font-size: 10pt;"&gt;22,778&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'; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;32,792&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'; font-size: 10pt;"&gt;(540&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'; 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'; font-size: 10pt;"&gt;55,570&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'; font-size: 10pt;"&gt;(680&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'; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 16%; 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'; 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; 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'; font-size: 10pt;"&gt;603&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'; 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'; font-size: 10pt;"&gt;1,198,933&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'; 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'; font-size: 10pt;"&gt;(6,134&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'; 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'; 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'; font-size: 10pt;"&gt;486,918&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'; 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'; font-size: 10pt;"&gt;(14,173&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'; 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'; 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'; font-size: 10pt;"&gt;1,685,851&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'; 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'; font-size: 10pt;"&gt;(20,307&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'; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: Calibri; 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'; font-size: 10pt;"&gt;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
    rather than underlying credit deterioration for any of the issuers. We believe it is more likely than not that we will be able to hold our debt securities with declines in value to maturity. Therefore, we anticipate full recovery of our debt
    securities&#x2019; amortized cost basis at maturity.&lt;/div&gt;
</us-gaap:InvestmentTextBlock>
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      contextRef="c20230101to20230331"
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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'; font-size: 10pt;"&gt;The following table summarizes the contract maturity of the available-for-sale securities we held as of March 31, 2023:&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', Times, serif; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;74&lt;/div&gt;
        &lt;/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'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;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'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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_f12cc57cfa544d218ac6c26f9aae5797"&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'; font-size: 10pt;"&gt;3&lt;/div&gt;
        &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'; 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;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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;&#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'; font-size: 10pt;"&gt;100&lt;/div&gt;
        &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'; font-size: 10pt;"&gt;%&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
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      contextRef="c20230101to20230331"
      id="Text_b7c74c13c32e406597a8b0ef49047c5a">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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', Times, serif; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold; text-indent: 6.5pt;"&gt;Amortized&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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="6" 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'; 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;" 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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; 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'; font-size: 10pt; font-weight: bold;"&gt;&lt;span style="text-indent: 0pt;"&gt;March 31, 2023&lt;/span&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="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'; 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;" 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'; 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;" 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'; 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;" 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'; 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'; font-size: 10pt;"&gt;&lt;span style="text-decoration: underline;"&gt;Available-for-sale debt securities:&lt;/span&gt;&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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;623,940&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;62&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(6,026&lt;/div&gt;
        &lt;/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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;617,976&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;247,629&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;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;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(1,283&lt;/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'; 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'; font-size: 10pt;"&gt;246,415&lt;/div&gt;
        &lt;/td&gt;

    &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'; 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'; font-size: 10pt;"&gt;556,394&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;62&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(3,738&lt;/div&gt;
        &lt;/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'; 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'; font-size: 10pt;"&gt;552,718&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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 style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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;" valign="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'; font-size: 10pt;"&gt;57,322&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'; font-size: 10pt;"&gt;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;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'; font-size: 10pt;"&gt;(498&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'; 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'; font-size: 10pt;"&gt;56,828&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: 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'; font-size: 10pt;"&gt;Total debt 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'; font-size: 10pt;"&gt;1,485,285&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'; font-size: 10pt;"&gt;197&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'; font-size: 10pt;"&gt;(11,545&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'; 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'; font-size: 10pt;"&gt;1,473,937&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%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Corporate debt 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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;200,661&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;336&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;(5,205&lt;/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'; 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'; font-size: 10pt;"&gt;195,792&lt;/div&gt;
        &lt;/td&gt;

    &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'; 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'; font-size: 10pt;"&gt;99,635&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;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;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(649&lt;/div&gt;
        &lt;/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'; 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'; font-size: 10pt;"&gt;99,242&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;257,651&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;364&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;(2,726&lt;/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'; 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'; font-size: 10pt;"&gt;255,289&lt;/div&gt;
        &lt;/td&gt;

    &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%; 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'; 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: #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'; font-size: 10pt;"&gt;14,564&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'; font-size: 10pt;"&gt;106&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'; font-size: 10pt;"&gt;(182&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'; 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'; font-size: 10pt;"&gt;14,488&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;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Total debt 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;" valign="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'; font-size: 10pt;"&gt;572,511&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'; font-size: 10pt;"&gt;1,062&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'; font-size: 10pt;"&gt;(8,762&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'; 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'; font-size: 10pt;"&gt;564,811&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: 2px; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 27pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Total available-for-sale 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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;2,057,796&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'; 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'; font-size: 10pt;"&gt;1,259&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'; 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'; font-size: 10pt;"&gt;(20,307&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'; 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'; 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'; font-size: 10pt;"&gt;2,038,748&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%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&lt;span style="text-decoration: underline;"&gt;Equity securities:&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;&#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;td colspan="1" style="vertical-align: bottom; width: 1%;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 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: 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'; font-size: 10pt;"&gt;Publicly traded 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(4,508&lt;/div&gt;
        &lt;/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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;7,389&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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 style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Privately held 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;" valign="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'; font-size: 10pt;"&gt;23,115&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'; font-size: 10pt;"&gt;25,001&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'; font-size: 10pt;"&gt;(5,125&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'; 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'; font-size: 10pt;"&gt;42,991&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: 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'; 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;&#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'; font-size: 10pt;"&gt;35,012&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'; font-size: 10pt;"&gt;25,001&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'; font-size: 10pt;"&gt;(9,633&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'; 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'; font-size: 10pt;"&gt;50,380&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;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 27pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Total available-for-sale debt and equity 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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;2,092,808&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'; 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'; font-size: 10pt;"&gt;26,260&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'; 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'; font-size: 10pt;"&gt;(29,940&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'; 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'; 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'; font-size: 10pt;"&gt;2,089,128&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="cfttable" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold; text-indent: 6.5pt;"&gt;Amortized&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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="6" 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'; 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;" 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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; 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'; font-size: 10pt; font-weight: bold;"&gt;&lt;span style="text-indent: 0pt;"&gt;December 31, 2022&lt;/span&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="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'; 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;" 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'; 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;" 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'; 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;" 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'; 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'; font-size: 10pt;"&gt;&lt;span style="text-decoration: underline;"&gt;Available-for-sale debt securities:&lt;/span&gt;&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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;513,790&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;23&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(4,365&lt;/div&gt;
        &lt;/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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;509,448&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;133,585&lt;/div&gt;
        &lt;/td&gt;

    &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'; 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'; font-size: 10pt;"&gt;(1,829&lt;/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'; 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'; font-size: 10pt;"&gt;131,756&lt;/div&gt;
        &lt;/td&gt;

    &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'; 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'; font-size: 10pt;"&gt;512,655&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;23&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(5,124&lt;/div&gt;
        &lt;/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'; 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'; font-size: 10pt;"&gt;507,554&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;57,484&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;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;&#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'; font-size: 10pt;"&gt;(686&lt;/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'; 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'; font-size: 10pt;"&gt;56,816&lt;/div&gt;
        &lt;/td&gt;

    &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%; 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'; 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'; font-size: 10pt;"&gt;6,008&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;&#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'; 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'; font-size: 10pt;"&gt;(14&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'; 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'; font-size: 10pt;"&gt;5,994&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;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Total debt 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;" valign="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'; font-size: 10pt;"&gt;1,223,522&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'; font-size: 10pt;"&gt;64&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'; font-size: 10pt;"&gt;(12,018&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'; 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'; font-size: 10pt;"&gt;1,211,568&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%; 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'; 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'; font-size: 10pt;"&gt;227,631&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;14&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(10,143&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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;217,502&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;34,339&lt;/div&gt;
        &lt;/td&gt;

    &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'; 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'; font-size: 10pt;"&gt;(1,040&lt;/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'; 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'; font-size: 10pt;"&gt;33,299&lt;/div&gt;
        &lt;/td&gt;

    &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'; 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'; font-size: 10pt;"&gt;245,030&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;(4,109&lt;/div&gt;
        &lt;/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'; 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'; font-size: 10pt;"&gt;240,921&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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 style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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;" valign="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'; font-size: 10pt;"&gt;18,314&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'; font-size: 10pt;"&gt;116&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'; font-size: 10pt;"&gt;(329&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'; 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'; font-size: 10pt;"&gt;18,101&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: 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'; font-size: 10pt;"&gt;Total debt 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'; font-size: 10pt;"&gt;525,314&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'; font-size: 10pt;"&gt;130&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'; font-size: 10pt;"&gt;(15,621&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'; 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'; font-size: 10pt;"&gt;509,823&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;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 27pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Total available-for-sale debt securities&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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;1,748,836&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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;194&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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(27,639&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'; 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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;1,721,391&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%; 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'; font-size: 10pt;"&gt;&lt;span style="text-decoration: underline;"&gt;Equity securities:&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;&#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%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Publicly traded equity securities included in other current assets (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'; 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'; 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%; 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'; 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'; 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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;(1,358&lt;/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'; 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'; 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'; font-size: 10pt;"&gt;10,539&lt;/div&gt;
        &lt;/td&gt;

    &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%; 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'; font-size: 10pt;"&gt;Privately held 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'; font-size: 10pt;"&gt;23,115&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'; font-size: 10pt;"&gt;17,257&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'; 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'; font-size: 10pt;"&gt;40,372&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;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: 9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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;" valign="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'; font-size: 10pt;"&gt;35,012&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'; font-size: 10pt;"&gt;17,257&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'; font-size: 10pt;"&gt;(1,358&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'; 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'; font-size: 10pt;"&gt;50,911&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: left; text-indent: 27pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Total available-for-sale debt 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'; 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'; font-size: 10pt;"&gt;1,783,848&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'; 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'; font-size: 10pt;"&gt;17,451&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'; 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'; font-size: 10pt;"&gt;(28,997&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'; 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'; 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'; font-size: 10pt;"&gt;1,772,302&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="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;Includes investments classified as cash
            equivalents in our condensed consolidated balance sheets.&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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;Our publicly traded equity securities are
            included in other current assets. We recognize publicly traded equity securities at fair value. In the three months ended&#160;March 31, 2023, we recognized a $3.2
            million unrealized loss in our condensed consolidated statements of operations related to a decrease in the fair value of our investments in publicly traded companies.&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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt;Our privately held equity securities are included in deposits and other assets. We recognize our privately held 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, which are Level 3 inputs&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt;. In the three months ended March 31, 2023, we recorded a
              net gain of $&lt;/span&gt;2.6&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt; million in our condensed
              consolidated statements of operations related to changes in the fair value of our investments in privately held companies.&lt;/span&gt;&lt;/div&gt;
        &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'; font-size: 10pt;"&gt;The following is a summary of our investments we consider to be temporarily impaired at March 31, 2023 (in thousands, except for number of investments):&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', Times, serif; 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; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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="6" 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'; font-size: 10pt; font-weight: bold;"&gt;Less than 12 Months of&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Temporary Impairment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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="6" 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'; font-size: 10pt; font-weight: bold;"&gt;More than 12 Months of&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Temporary Impairment&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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="6" 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'; font-size: 10pt; font-weight: bold;"&gt;Total Temporary&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Impairment&lt;/div&gt;
        &lt;/td&gt;

    &lt;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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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'; 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;" 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'; font-size: 10pt; font-weight: bold;"&gt;Estimated&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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;" 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'; font-size: 10pt; font-weight: bold;"&gt;Unrealized&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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;" 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'; font-size: 10pt; font-weight: bold;"&gt;Estimated&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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;" 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'; font-size: 10pt; font-weight: bold;"&gt;Unrealized&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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;" 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'; font-size: 10pt; font-weight: bold;"&gt;Estimated&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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;" 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'; font-size: 10pt; font-weight: bold;"&gt;Unrealized&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; 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: 16%; 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'; 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'; font-size: 10pt;"&gt;361&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;434,500&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(1,697&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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;291,713&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(9,534&lt;/div&gt;
        &lt;/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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;726,213&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(11,231&lt;/div&gt;
        &lt;/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'; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 16%;" valign="bottom"&gt;
          &lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;68&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;138,211&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;(424&lt;/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'; 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'; font-size: 10pt;"&gt;70,965&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;(1,508&lt;/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'; 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'; font-size: 10pt;"&gt;209,176&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;(1,932&lt;/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'; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 16%; 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'; 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'; 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;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;603,444&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(3,873&lt;/div&gt;
        &lt;/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'; 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'; font-size: 10pt;"&gt;91,448&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(2,591&lt;/div&gt;
        &lt;/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'; 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'; font-size: 10pt;"&gt;694,892&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;(6,464&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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 16%; 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'; 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;" valign="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'; font-size: 10pt;"&gt;110&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'; font-size: 10pt;"&gt;22,778&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'; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;32,792&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'; font-size: 10pt;"&gt;(540&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'; 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'; font-size: 10pt;"&gt;55,570&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'; font-size: 10pt;"&gt;(680&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'; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;

  &lt;tr&gt;

    &lt;td style="vertical-align: bottom; width: 16%; 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'; 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; 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'; font-size: 10pt;"&gt;603&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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

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          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;1,198,933&lt;/div&gt;
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    &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'; font-size: 10pt;"&gt;$&lt;/div&gt;
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    &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'; font-size: 10pt;"&gt;(6,134&lt;/div&gt;
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    &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'; 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'; 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'; font-size: 10pt;"&gt;486,918&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'; 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'; font-size: 10pt;"&gt;(14,173&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'; 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'; 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'; font-size: 10pt;"&gt;1,685,851&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'; 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'; font-size: 10pt;"&gt;(20,307&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'; font-size: 10pt;"&gt;)&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


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&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;7.&#160; 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'; font-size: 10pt;"&gt;The following tables present the major security types we held at March 31, 2023 and December 31, 2022 that we regularly measure and
    carry at fair value. 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 security&#x2019;s 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', Times, serif; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;At&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;March 31, 2023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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'; 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'; 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'; 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;" 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'; 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'; 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'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;276,352&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;276,352&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;813,768&lt;/div&gt;
        &lt;/td&gt;

    &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'; 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'; font-size: 10pt;"&gt;813,768&lt;/div&gt;
        &lt;/td&gt;

    &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-right: 6pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;345,657&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;345,657&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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'; 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'; font-size: 10pt;"&gt;808,007&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'; font-size: 10pt;"&gt;808,007&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'; 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'; 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'; font-size: 10pt;"&gt;71,316&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;71,316&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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&gt;
            &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Publicly traded equity securities included in other current assets (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'; font-size: 10pt;"&gt;7,389&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'; font-size: 10pt;"&gt;7,389&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'; 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: 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'; 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'; 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'; font-size: 10pt;"&gt;2,322,489&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'; 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'; font-size: 10pt;"&gt;1,091,748&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'; 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'; font-size: 10pt;"&gt;1,230,741&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', Times, serif; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;At&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;December 31, 2022&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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'; 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'; 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'; 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;" 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'; 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'; 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'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;211,655&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;211,655&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;726,950&lt;/div&gt;
        &lt;/td&gt;

    &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'; 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'; font-size: 10pt;"&gt;726,950&lt;/div&gt;
        &lt;/td&gt;

    &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-right: 6pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;165,055&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;165,055&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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'; 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'; font-size: 10pt;"&gt;748,475&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;748,475&lt;/div&gt;
        &lt;/td&gt;

    &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'; 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'; 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'; font-size: 10pt;"&gt;74,917&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;74,917&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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: left; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;5,994&lt;/div&gt;
        &lt;/td&gt;

    &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'; 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'; font-size: 10pt;"&gt;5,994&lt;/div&gt;
        &lt;/td&gt;

    &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: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Publicly traded equity securities included in other current assets (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'; font-size: 10pt;"&gt;10,539&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'; font-size: 10pt;"&gt;10,539&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'; 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'; 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'; 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'; font-size: 10pt;"&gt;1,943,585&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'; 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'; font-size: 10pt;"&gt;970,669&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'; 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'; font-size: 10pt;"&gt;972,916&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;div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;The following footnotes reference lines in our condensed consolidated balance sheets:&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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;Included in cash and cash equivalents in our
            condensed consolidated balance sheets.&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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;Included in short-term investments in our
            condensed consolidated balance sheets.&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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;$1.0 million was included in cash and cash equivalents in our condensed consolidated balance sheets, with the difference included in short-term investments in our condensed
            consolidated balance sheets.&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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;Included in other current assets in our
            condensed consolidated balance sheets.&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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;$11.0 million was included in cash and cash equivalents in our condensed consolidated balance sheets, with the difference included in short-term investments in our condensed
            consolidated balance sheets.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: Calibri; font-size: 12pt;"&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="text-align: left; margin-left: 36pt; color: #000000; font-family: 'Times New Roman'; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Our 0.125% Notes and 0% Notes had a fair value of $506.3 million and $578.4 million at March 31, 2023, respectively.
    Our 0.125% Notes and 0% Notes had a
    fair value of $498.9 million and $587.3
    million at December 31, 2022, 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:FairValueDisclosuresTextBlock>
    <us-gaap:FairValueAssetsMeasuredOnRecurringBasisTextBlock
      contextRef="c20230101to20230331"
      id="Text_3fc22c693e28451987436214b4939105">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;The following tables present the major security types we held at March 31, 2023 and December 31, 2022 that we regularly measure and
    carry at fair value. 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 security&#x2019;s 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', Times, serif; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;At&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;March 31, 2023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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'; 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'; 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'; 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;" 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'; 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'; 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'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;276,352&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;276,352&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;813,768&lt;/div&gt;
        &lt;/td&gt;

    &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'; 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'; font-size: 10pt;"&gt;813,768&lt;/div&gt;
        &lt;/td&gt;

    &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-right: 6pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;345,657&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;345,657&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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'; 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'; font-size: 10pt;"&gt;808,007&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'; font-size: 10pt;"&gt;808,007&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'; 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'; 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'; font-size: 10pt;"&gt;71,316&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;71,316&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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&gt;
            &lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Publicly traded equity securities included in other current assets (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'; font-size: 10pt;"&gt;7,389&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'; font-size: 10pt;"&gt;7,389&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'; 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: 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'; 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'; 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'; font-size: 10pt;"&gt;2,322,489&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'; 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'; font-size: 10pt;"&gt;1,091,748&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'; 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'; font-size: 10pt;"&gt;1,230,741&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', Times, serif; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;At&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;December 31, 2022&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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'; 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'; 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'; 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;" 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'; 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'; 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'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;211,655&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;211,655&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;726,950&lt;/div&gt;
        &lt;/td&gt;

    &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'; 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'; font-size: 10pt;"&gt;726,950&lt;/div&gt;
        &lt;/td&gt;

    &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-right: 6pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;165,055&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;165,055&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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'; 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'; font-size: 10pt;"&gt;748,475&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;748,475&lt;/div&gt;
        &lt;/td&gt;

    &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'; 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'; 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'; font-size: 10pt;"&gt;74,917&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;74,917&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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: left; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;5,994&lt;/div&gt;
        &lt;/td&gt;

    &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'; 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'; font-size: 10pt;"&gt;5,994&lt;/div&gt;
        &lt;/td&gt;

    &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: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Publicly traded equity securities included in other current assets (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'; font-size: 10pt;"&gt;10,539&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'; font-size: 10pt;"&gt;10,539&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'; 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'; 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'; 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'; font-size: 10pt;"&gt;1,943,585&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'; 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'; font-size: 10pt;"&gt;970,669&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'; 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'; font-size: 10pt;"&gt;972,916&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;div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;The following footnotes reference lines in our condensed consolidated balance sheets:&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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;Included in cash and cash equivalents in our
            condensed consolidated balance sheets.&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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;Included in short-term investments in our
            condensed consolidated balance sheets.&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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;$1.0 million was included in cash and cash equivalents in our condensed consolidated balance sheets, with the difference included in short-term investments in our condensed
            consolidated balance sheets.&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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;Included in other current assets in our
            condensed consolidated balance sheets.&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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;$11.0 million was included in cash and cash equivalents in our condensed consolidated balance sheets, with the difference included in short-term investments in our condensed
            consolidated balance sheets.&lt;/div&gt;
        &lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
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&lt;div style="text-align: left; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;8. 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'; 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 condensed 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'; 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.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;For the three months ended&#160;March 31, 2023 and 2022, 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: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"&gt;Employee Stock Options:&lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Three Months Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;March 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;2023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;"&gt;2022&lt;/div&gt;
        &lt;/td&gt;

    &lt;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'; 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'; font-size: 10pt;"&gt;3.6&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'; 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'; 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%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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'; 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'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;47.5&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'; 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'; font-size: 10pt;"&gt;55.2&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'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;6.3 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'; font-size: 10pt;"&gt;6.3 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;/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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; font-family: 'Times New Roman'; font-size: 10pt;"&gt;*&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman'; font-size: 10pt;"&gt;In 2021, our Compensation Committee approved
            an amendment to the 2011 Equity Incentive Plan, or 2011 Plan, and the &lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt;2020 Equity Incentive Plan, or&lt;/span&gt; 2020 Plan, that increased the contractual term of stock
            options granted under these plans from seven years to ten years for stock options granted on January 1, 2022 and thereafter. We determined that we are unable to rely on our historical exercise data as a basis for estimating the expected
            life of stock options granted to employees following this change because the contractual term changed and we have no other means to reasonably estimate future exercise behavior. We therefore used the simplified method for determining the
            expected life of stock options granted to employees in the three months ended&#160;March 31, 2023 and 2022. Under the simplified method, we calculate the expected term as the average of the time-to-vesting and the contractual life of the options. As we gain additional
            historical information, we will transition to calculating our expected term based on our historical exercise patterns.&#160;&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'; font-size: 10pt; font-style: italic;"&gt;ESPP:&lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Three Months Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;March 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;2023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;"&gt;2022&lt;/div&gt;
        &lt;/td&gt;

    &lt;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'; 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'; font-size: 10pt;"&gt;5.2&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'; 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'; 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'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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'; 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'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;36.7&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'; 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'; font-size: 10pt;"&gt;50.2&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'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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: Calibri; 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'; font-size: 10pt; font-style: italic;"&gt;RSUs:&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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. The RSUs we granted after June 2020 to our board of directors fully vest after one year. The weighted-average grant date fair value of RSUs granted to employees for the three months ended&#160;March 31, 2023 was $39.85
    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: left; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"&gt;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; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Beginning in 2020, we added PRSU awards to the compensation for our Chief Executive Officer, Dr. Brett Monia. In 2022, we added PRSU awards to the
    compensation for our other Section 16 officers. Beginning in 2023, we added PRSU awards to the compensation for all executive officers.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &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'; font-size: 10pt;"&gt;Under the terms of the PRSUs we granted in 2020 through 2022, &lt;span style="-sec-ix-hidden:Fact_3ea144f70898401099a1731ad0c7e39f"&gt;&lt;span style="-sec-ix-hidden:Fact_b531c97d5a394e3f8a5454ecd82ddb93"&gt;&lt;span style="-sec-ix-hidden:Fact_b2b6dbe875764e78b9cce0b8464216dd"&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 percentto 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; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Under the terms of the PRSUs we granted in 2023, 100 percent of the PRSUs may vest at the end of the three-year performance period based on our relative
    TSR as compared to a peer group of companies and as measured at the end of the 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 200 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; font-family: 'Times New Roman'; font-size: 10pt;"&gt;We determined the fair value of the PRSUs using a Monte Carlo model because the performance target is based on our relative TSR, which represents a
    market condition. The weighted-average grant date fair value of PRSUs granted to our executive officers for the three months ended&#160;March 31, 2023 and 2022 were $58.99 and $42.28 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'; font-size: 10pt;"&gt;The following table summarizes stock-based compensation expense for the three months ended&#160;March 31, 2023 and 2022 (in thousands):&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;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Three Months Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;March 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;2023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;"&gt;2022&lt;/div&gt;
        &lt;/td&gt;

    &lt;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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;160&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Research, development and patent 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;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;19,567&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;19,082&lt;/div&gt;
        &lt;/td&gt;

    &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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Selling, general and administrative expense&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'; font-size: 10pt;"&gt;7,262&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'; font-size: 10pt;"&gt;6,994&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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;"&gt;26,948&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'; 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'; font-size: 10pt;"&gt;26,236&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: Calibri; 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'; font-size: 10pt;"&gt;As of March 31, 2023,
    total unrecognized estimated stock-based compensation expense related to non-vested stock options, RSUs and PRSUs was $60.2 million, $79.1 million and $9.5 million, respectively. Our
    actual expenses may differ from these estimates because we will adjust our unrecognized stock-based compensation expense for future forfeitures, including any PRSUs that do not vest. We expect to recognize the cost of stock-based compensation expense
    related to our non-vested stock options, RSUs and PRSUs over a weighted average amortization period of 1.4 years, 1.8 years and 2.2 years, respectively.&lt;/div&gt;
</us-gaap:DisclosureOfCompensationRelatedCostsShareBasedPaymentsTextBlock>
    <us-gaap:ShareBasedCompensationOptionAndIncentivePlansPolicy
      contextRef="c20230101to20230331"
      id="Text_c5ce94c54d424a5d9c24152ec62f851f">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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 condensed 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'; 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.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; 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;
</us-gaap:ShareBasedCompensationOptionAndIncentivePlansPolicy>
    <us-gaap:ScheduleOfShareBasedPaymentAwardStockOptionsValuationAssumptionsTableTextBlock
      contextRef="c20230101to20230331"
      id="Text_9422cf9a8132473fb2f59888393f984a">
&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'; font-size: 10pt; font-style: italic;"&gt;Employee Stock Options:&lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Three Months Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;March 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;2023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;"&gt;2022&lt;/div&gt;
        &lt;/td&gt;

    &lt;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'; 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'; font-size: 10pt;"&gt;3.6&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'; 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'; 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%; background-color: #CCEEFF; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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'; 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'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;47.5&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'; 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'; font-size: 10pt;"&gt;55.2&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'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;6.3 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'; font-size: 10pt;"&gt;6.3 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;/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', Times, serif; font-size: 10pt; width: 100%; text-align: left; color: #000000;"&gt;


  &lt;tr&gt;

    &lt;td style="width: 18pt; vertical-align: top; font-family: 'Times New Roman'; font-size: 10pt;"&gt;*&lt;/td&gt;

    &lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;
          &lt;div style="font-family: 'Times New Roman'; font-size: 10pt;"&gt;In 2021, our Compensation Committee approved
            an amendment to the 2011 Equity Incentive Plan, or 2011 Plan, and the &lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt;2020 Equity Incentive Plan, or&lt;/span&gt; 2020 Plan, that increased the contractual term of stock
            options granted under these plans from seven years to ten years for stock options granted on January 1, 2022 and thereafter. We determined that we are unable to rely on our historical exercise data as a basis for estimating the expected
            life of stock options granted to employees following this change because the contractual term changed and we have no other means to reasonably estimate future exercise behavior. We therefore used the simplified method for determining the
            expected life of stock options granted to employees in the three months ended&#160;March 31, 2023 and 2022. Under the simplified method, we calculate the expected term as the average of the time-to-vesting and the contractual life of the options. As we gain additional
            historical information, we will transition to calculating our expected term based on our historical exercise patterns.&#160;&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; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"&gt;ESPP:&lt;/div&gt;

&lt;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Three Months Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;March 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;2023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;"&gt;2022&lt;/div&gt;
        &lt;/td&gt;

    &lt;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'; 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'; font-size: 10pt;"&gt;5.2&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'; 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'; 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'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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'; 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'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;36.7&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'; 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'; font-size: 10pt;"&gt;50.2&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'; 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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;The following table summarizes stock-based compensation expense for the three months ended&#160;March 31, 2023 and 2022 (in thousands):&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;table cellpadding="0" cellspacing="0" class="cfttable" style="font-family: 'Times New Roman', Times, serif; 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;Three Months Ended&lt;/div&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;March 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; white-space: nowrap;" valign="bottom"&gt;
          &lt;div style="text-align: center; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;2023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; 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'; font-size: 10pt; font-weight: bold;"&gt;2022&lt;/div&gt;
        &lt;/td&gt;

    &lt;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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;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;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;160&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Research, development and patent 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;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;19,567&lt;/div&gt;
        &lt;/td&gt;

    &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'; font-size: 10pt;"&gt;19,082&lt;/div&gt;
        &lt;/td&gt;

    &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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Selling, general and administrative expense&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'; font-size: 10pt;"&gt;7,262&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'; font-size: 10pt;"&gt;6,994&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: left; text-indent: -9pt; margin-left: 9pt; color: #000000; font-family: 'Times New Roman'; 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'; 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'; font-size: 10pt;"&gt;26,948&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'; 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'; font-size: 10pt;"&gt;26,236&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:EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1
      contextRef="c20230101to20230331_AwardTypeAxis_RestrictedStockUnitsRSUMember"
      id="Fact_94356ff2a4564b669110ba6365630dc9">P1Y9M18D</us-gaap:EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1>
    <us-gaap:EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1
      contextRef="c20230101to20230331_AwardTypeAxis_PerformanceSharesMember"
      id="Fact_715166969b8f40d5bb56857e5eca4ce6">P2Y2M12D</us-gaap:EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1>
    <us-gaap:IncomeTaxDisclosureTextBlock
      contextRef="c20230101to20230331"
      id="Text_5d168265bebe4eef9cbf660ffa2537c4">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: left; text-indent: -36pt; margin-left: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;9.&#160; 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'; font-size: 10pt;"&gt;Beginning in 2022, the Tax Cuts and Jobs Act of 2017, or TCJA, requires taxpayers to amortize research and development expenditures over
    five years pursuant to Internal Revenue Code, or IRC, Section 174. Additionally, we expect to reflect the royalty purchase agreement with Royalty Pharma as a taxable sale, requiring us to include the proceeds from the sale, net of currently deductible
    issuance costs, as taxable income in 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'; font-size: 10pt;"&gt;We recorded income tax expense of $11.4
    million and $1.1 million for the three months ended March 31, 2023 and 2022, respectively. The increase in income tax expense for the three
    months ended March 31, 2023, compared to the same period in 2022, relates primarily to the impact of the Royalty Pharma transaction. &lt;/div&gt;
</us-gaap:IncomeTaxDisclosureTextBlock>
    <us-gaap:IncomeTaxExpenseBenefit
      contextRef="c20230101to20230331"
      decimals="-5"
      id="Fact_4b3f01cf09d94228871fc7985d1e7730"
      unitRef="U002">11400000</us-gaap:IncomeTaxExpenseBenefit>
    <us-gaap:IncomeTaxExpenseBenefit
      contextRef="c20220101to20220331"
      decimals="-5"
      id="Fact_60f4bba6820147aa9e2ebb581601b708"
      unitRef="U002">1100000</us-gaap:IncomeTaxExpenseBenefit>
    <us-gaap:OtherLiabilitiesDisclosureTextBlock
      contextRef="c20230101to20230331"
      id="Text_f2a697cc2a48421a914d3e69877cc71e">
&lt;div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;10. Liability Related to Sale of Future 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'; font-size: 10pt;"&gt;In January 2023, we entered into a royalty purchase agreement with Royalty Pharma to monetize a portion of our future SPINRAZA and
    pelacarsen royalties we are entitled to under our arrangements with Biogen and Novartis, respectively. As a result, we received an upfront payment of $500
    million and we are eligible to receive up to $625 million in additional milestone payments. Under the terms of the agreement, Royalty Pharma will
    receive 25 percent of our SPINRAZA royalty payments from 2023 through 2027, increasing to 45 percent of royalty payments in 2028, on up to $1.5 billion in annual sales. In
    addition, Royalty Pharma will receive 25 percent of any future royalty payments on pelacarsen, our medicine in development to treat patients
    with elevated lipoprotein(a), or Lp(a), and cardiovascular disease. Royalty Pharma&#x2019;s royalty interest in SPINRAZA will revert to us after total SPINRAZA royalty payments to Royalty Pharma reach either $475 million or $550 million, depending on the timing and occurrence of FDA approval of
    pelacarsen.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;We recorded the upfront payment of $500
    million as a liability related to the sale of future royalties, net of transaction costs of $10.4 million, which we are amortizing over the
    estimated life of the arrangement using the effective interest rate method. We recognize royalty revenue in the period in which the counterparty sells the related product and recognizes the related revenue. We record royalty payments made to Royalty
    Pharma as a reduction of the liability.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;We estimate the effective interest rate used to record interest expense under this agreement based on the estimate of future royalty
    payments to Royalty Pharma. As of March 31, 2023, the estimated effective interest rate under the agreement was 13.5 percent.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;The following is a summary of our liability related to sale of future royalties for the three
    months ended March 31, 2023 (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', Times, serif; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Proceeds from sale of future royalties&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="font-family: 'Times New Roman'; font-size: 10pt;"&gt;500,000&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Interest expense related to sale of future royalties&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="font-family: 'Times New Roman'; font-size: 10pt;"&gt;15,363&lt;/div&gt;
        &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;/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; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Liability related to sale of future royalties as of March 31, 2023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="font-family: 'Times New Roman'; font-size: 10pt;"&gt;515,363&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Net issuance costs related to sale of future royalties as of March 31, 2023&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="font-family: 'Times New Roman'; font-size: 10pt;"&gt;(10,282&lt;/div&gt;
        &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="font-family: 'Times New Roman'; 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; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Net liability related to sale of future royalties as of March 31, 2023&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="font-family: 'Times New Roman'; 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="font-family: 'Times New Roman'; font-size: 10pt;"&gt;505,081&lt;/div&gt;
        &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;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;

&lt;div style="text-align: left; font-family: Calibri; 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'; font-size: 10pt;"&gt;There are numerous factors, most of which are not within our control, that could materially impact the amount and timing of royalty
    payments from Biogen and Novartis, and result in changes to our estimate of future royalty payments to Royalty Pharma. Such factors include, but are not limited to the commercial sales of SPINRAZA, the regulatory approval and commercial sales of
    pelacarsen, competing products or other significant events.&lt;/div&gt;
</us-gaap:OtherLiabilitiesDisclosureTextBlock>
    <ions:UpfrontRoyaltyPaymentReceived
      contextRef="c20230101to20230131_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember"
      decimals="-6"
      id="Fact_378c023c31584e55b0617bdf49309947"
      unitRef="U002">500000000</ions:UpfrontRoyaltyPaymentReceived>
    <ions:MaximumAmountOfPaymentsReceivableForAdditionalMilestones
      contextRef="c20230331_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember"
      decimals="-6"
      id="Fact_45c4a4d71b5f46aa8fc6a9fd8e84328e"
      unitRef="U002">625000000</ions:MaximumAmountOfPaymentsReceivableForAdditionalMilestones>
    <ions:PercentageOfRoyaltyPaymentsPaidOnAnnualSalesOfMedicine
      contextRef="c20230331_ProductOrServiceAxis_SpinrazaMember_RangeAxis_MinimumMember_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember"
      decimals="2"
      id="Fact_01f145be530749a2b5f41c92469f3150"
      unitRef="U003">0.25</ions:PercentageOfRoyaltyPaymentsPaidOnAnnualSalesOfMedicine>
    <ions:PercentageOfRoyaltyPaymentsPaidOnAnnualSalesOfMedicine
      contextRef="c20230331_ProductOrServiceAxis_SpinrazaMember_RangeAxis_MaximumMember_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember"
      decimals="2"
      id="Fact_4defe32cd3804cbb97e4c7a2e3a297be"
      unitRef="U003">0.45</ions:PercentageOfRoyaltyPaymentsPaidOnAnnualSalesOfMedicine>
    <ions:MaximumAmountOfAnnualSalesOnWhichRoyaltyPaymentsArePaid
      contextRef="c20230331_ProductOrServiceAxis_SpinrazaMember_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember"
      decimals="-8"
      id="Fact_4af0123d3f9a49d28566cdb7b703162e"
      unitRef="U002">1500000000</ions:MaximumAmountOfAnnualSalesOnWhichRoyaltyPaymentsArePaid>
    <ions:PercentageOfRoyaltyPaymentsPaidOnAnnualSalesOfMedicine
      contextRef="c20230331_ProductOrServiceAxis_PelacarsenMember_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember"
      decimals="2"
      id="Fact_5ab159c91cd6498eabdc7aec74f5b116"
      unitRef="U003">0.25</ions:PercentageOfRoyaltyPaymentsPaidOnAnnualSalesOfMedicine>
    <ions:MaximumRoyaltyPaymentsMadeBeforeRoyaltyInterestRevertsBack
      contextRef="c20230331_ProductOrServiceAxis_SpinrazaMember_RangeAxis_MinimumMember_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember"
      decimals="-6"
      id="Fact_8efbfdbd4aec4c57ba48a38ed1338a40"
      unitRef="U002">475000000</ions:MaximumRoyaltyPaymentsMadeBeforeRoyaltyInterestRevertsBack>
    <ions:MaximumRoyaltyPaymentsMadeBeforeRoyaltyInterestRevertsBack
      contextRef="c20230331_ProductOrServiceAxis_SpinrazaMember_RangeAxis_MaximumMember_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember"
      decimals="-6"
      id="Fact_d8115145c7914c85b8aa1e8af6fd697a"
      unitRef="U002">550000000</ions:MaximumRoyaltyPaymentsMadeBeforeRoyaltyInterestRevertsBack>
    <ions:UpfrontRoyaltyPaymentReceived
      contextRef="c20230101to20230131_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember"
      decimals="-6"
      id="Fact_9289646b66ea4d879d32f2749df14834"
      unitRef="U002">500000000</ions:UpfrontRoyaltyPaymentReceived>
    <ions:PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties
      contextRef="c20230101to20230331_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember"
      decimals="-5"
      id="Fact_b8a78efb0bd340eb9b74a4c718aade51"
      unitRef="U002">10400000</ions:PaymentsForTransactionCostsRelatedToSaleOfFutureRoyalties>
    <us-gaap:DebtInstrumentInterestRateEffectivePercentage
      contextRef="c20230331_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember"
      decimals="3"
      id="Fact_b086ad26f3df4c96a5fb5a381fd3f7e6"
      unitRef="U003">0.135</us-gaap:DebtInstrumentInterestRateEffectivePercentage>
    <us-gaap:OtherNoncurrentLiabilitiesTableTextBlock
      contextRef="c20230101to20230331"
      id="Text_96e6cdff125b48ec820d34ebadba6671">
&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;The following is a summary of our liability related to sale of future royalties for the three
    months ended March 31, 2023 (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', Times, serif; font-size: 10pt; text-align: left; color: #000000; width: 100%;"&gt;


  &lt;tr&gt;

    &lt;td style="vertical-align: top; width: 88%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Proceeds from sale of future royalties&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="font-family: 'Times New Roman'; font-size: 10pt;"&gt;500,000&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Interest expense related to sale of future royalties&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="font-family: 'Times New Roman'; font-size: 10pt;"&gt;15,363&lt;/div&gt;
        &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;/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; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Liability related to sale of future royalties as of March 31, 2023&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;&#160;&lt;/td&gt;

    &lt;td colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="font-family: 'Times New Roman'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="font-family: 'Times New Roman'; font-size: 10pt;"&gt;515,363&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="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%; padding-bottom: 2px;" valign="bottom"&gt;
          &lt;div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Net issuance costs related to sale of future royalties as of March 31, 2023&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="font-family: 'Times New Roman'; font-size: 10pt;"&gt;(10,282&lt;/div&gt;
        &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="font-family: 'Times New Roman'; 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; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; font-family: 'Times New Roman'; font-size: 10pt;"&gt;Net liability related to sale of future royalties as of March 31, 2023&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="font-family: 'Times New Roman'; 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="font-family: 'Times New Roman'; font-size: 10pt;"&gt;505,081&lt;/div&gt;
        &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;&#160;&lt;/td&gt;

  &lt;/tr&gt;


&lt;/table&gt;
</us-gaap:OtherNoncurrentLiabilitiesTableTextBlock>
    <ions:ProceedsFromSaleOfFutureRoyalties
      contextRef="c20230101to20230331_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember"
      decimals="-3"
      id="Fact_7a91cc925cbe4e289100163fed10eb8f"
      unitRef="U002">500000000</ions:ProceedsFromSaleOfFutureRoyalties>
    <ions:InterestExpenseRelatedToSaleOfFutureRoyalties
      contextRef="c20230101to20230331_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember"
      decimals="-3"
      id="Fact_8e2a0dc656c042c0beb05848a9d90cc8"
      unitRef="U002">15363000</ions:InterestExpenseRelatedToSaleOfFutureRoyalties>
    <ions:LiabilityRelatedToSaleOfFutureRoyaltiesGross
      contextRef="c20230331_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember"
      decimals="-3"
      id="Fact_bc68084a14554c4b9e5d028dcee5c291"
      unitRef="U002">515363000</ions:LiabilityRelatedToSaleOfFutureRoyaltiesGross>
    <us-gaap:DeferredFinanceCostsNet
      contextRef="c20230331_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember"
      decimals="-3"
      id="Fact_c211cdd46ff84aefa16bbfccaf2b3ea6"
      unitRef="U002">10282000</us-gaap:DeferredFinanceCostsNet>
    <ions:LiabilityRelatedToSaleOfFutureRoyaltiesNet
      contextRef="c20230331_TypeOfArrangementAxis_RoyaltyPurchaseAgreementMember"
      decimals="-3"
      id="Fact_b429946842f746a59ab4c99405afe9a0"
      unitRef="U002">505081000</ions:LiabilityRelatedToSaleOfFutureRoyaltiesNet>
    <us-gaap:DebtDisclosureTextBlock
      contextRef="c20230101to20230331"
      id="Text_932c025cb1a047c69adb81a74fc1d444">
&lt;div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;11. 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'; 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; 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'; font-size: 10pt;"&gt;At March 31, 2023, we had the following &lt;span style="font-family: Times; font-size: 10pt;"&gt;0%&lt;/span&gt; Notes outstanding (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', Times, serif; 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="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'; font-size: 10pt; font-weight: bold;"&gt;0% 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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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'; font-size: 10pt;"&gt;9.5&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'; 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'; font-size: 10pt;"&gt;&lt;span style="-sec-ix-hidden:Fact_edbb9fb31e834f86ad026d22e567df04"&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'; 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'; 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'; 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'; 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'; 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'; 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'; 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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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: Calibri; 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'; 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-family: Times; font-size: 10pt;"&gt;0%&lt;/span&gt;
    Notes by increasing the effective conversion price on our &lt;span style="font-family: Times; font-size: 10pt;"&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-family: Times; font-size: 10pt;"&gt;0%&#160;&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-family: Times; font-size: 10pt;"&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-family: Times; font-size: 10pt;"&gt;0%&lt;/span&gt; Notes. The note hedges will expire upon maturity of the &lt;span style="font-family: Times; font-size: 10pt;"&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-family: Times; font-size: 10pt;"&gt;0%&lt;/span&gt; Notes. The holders of the &lt;span style="font-family: Times; font-size: 10pt;"&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; font-family: 'Times New Roman'; 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 condensed
    consolidated balance sheets. Refer to Part IV, Item 15, Note 1 of our audited financial statements included in our Annual Report on Form 10-K for the year ended December 31, 2022 for our Call Spread accounting policy. 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'; 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; font-family: 'Times New Roman'; font-size: 10pt;"&gt;At March 31, 2023, we had the following 0.125%
    Notes outstanding with interest payable semi-annually (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', Times, serif; 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="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'; 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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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'; font-size: 10pt;"&gt;3.8&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: top; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;&lt;span style="-sec-ix-hidden:Fact_9ad2e8b4fef74d3cab598aa38f5df4fd"&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'; 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'; 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'; 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'; 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'; 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'; 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'; 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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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: Calibri; 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'; font-size: 10pt;"&gt;&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt;In conjunction with the issuance of our &lt;/span&gt;0.125%&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; 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-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt;. We increased our effective conversion price to $123.38 with the same number of underlying shares as our &lt;/span&gt;0.125%&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt; Notes. The call spread cost us $&lt;/span&gt;52.6&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt; million, of which $&lt;/span&gt;108.7&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt; million was for the note hedge purchase, offset by $&lt;/span&gt;56.1&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt; million we received for selling the warrants. Similar to our &lt;/span&gt;0.125% Notes&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; 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-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt;. The note hedges will expire upon maturity of the &lt;/span&gt;0.125% Notes&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; 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-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt;. The holders of
      the &lt;/span&gt;0.125% Notes&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; 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'; 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
    condensed consolidated balance sheets. 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'; 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; font-family: 'Times New Roman'; font-size: 10pt;"&gt;&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt;The &lt;/span&gt;&lt;span style="font-family: Times; font-size: 10pt;"&gt;0%&lt;/span&gt;&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt; and &lt;/span&gt;0.125%&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt; 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 &lt;/span&gt;100 percent&lt;span style="font-family: 'Times New Roman'; font-size: 10pt; color: #000000;"&gt; of the principal amount of the notes to be purchased, plus any accrued and unpaid interest.&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: justify; text-indent: 36pt; font-family: 'Times New Roman'; font-size: 10pt;"&gt;At March 31, 2023, we had the following &lt;span style="font-family: Times; font-size: 10pt;"&gt;0%&lt;/span&gt; Notes outstanding (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', Times, serif; 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="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'; font-size: 10pt; font-weight: bold;"&gt;0% 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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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'; font-size: 10pt;"&gt;9.5&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'; 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'; font-size: 10pt;"&gt;&lt;span style="-sec-ix-hidden:Fact_edbb9fb31e834f86ad026d22e567df04"&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'; 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'; 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'; 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'; 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'; 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'; 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'; 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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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;
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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'; font-size: 10pt;"&gt;At March 31, 2023, we had the following 0.125%
    Notes outstanding with interest payable semi-annually (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', Times, serif; 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="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'; 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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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'; font-size: 10pt;"&gt;3.8&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: top; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="text-align: justify; color: #000000; font-family: 'Times New Roman'; 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'; font-size: 10pt;"&gt;&lt;span style="-sec-ix-hidden:Fact_9ad2e8b4fef74d3cab598aa38f5df4fd"&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'; 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'; 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'; 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'; 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'; 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'; 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'; 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'; 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'; font-size: 10pt;"&gt;$&lt;/div&gt;
        &lt;/td&gt;

    &lt;td colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;" valign="bottom"&gt;
          &lt;div style="color: #000000; font-family: 'Times New Roman'; 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'; 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'; 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="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;"&gt;12. 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'; 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 we consider the potential loss from any legal proceeding to be probable and we can reasonably estimate the amount, we accrue a liability for the estimated loss. The outcome of
    any proceeding is not determinable in advance. Therefore, we are required to use significant judgment to determine the probability of a loss and whether the amount of the loss is reasonably estimable. Our assessment of a potential liability and the
    amount of accruals we 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'; 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 Shumacher Action. The complaint names Ionis&#x2019; board of directors, or the Board, as defendants and names Ionis as a nominal defendant. The Shumacher Action Plaintiff
    asserts a breach of fiduciary duty claim against the Board for awarding and receiving allegedly excessive compensation. The Shumacher Action Plaintiff also asserts an unjust enrichment claim against the non-executive 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. On March 18, 2022, Ionis and the Board moved to dismiss the complaint.
    On May 24, 2022, the parties entered into a Stipulation and Agreement of Compromise, Settlement and Release.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;On May 25, 2022, another purported stockholder of Ionis filed a stockholder derivative complaint also in the Delaware Court of Chancery
    captioned Robert S. Cohen, et al. v. Joseph Loscalzo, et al., C.A. No. 2022-0453, or the Cohen Action. The complaint names the Board as defendants and names Ionis as a nominal defendant. The Cohen Action Plaintiff asserts claims for breach of fiduciary
    duty, unjust enrichment, aiding and abetting breaches of fiduciary duty, and waste against the Board for awarding and receiving allegedly excessive non-executive director compensation for the years 2018, 2019, and 2020. On June 2, 2022, the Cohen
    Action Plaintiff filed a motion to consolidate the related Cohen Action and Shumacher Action. On July 5, 2022, the Court denied the motion to consolidate in favor of the settlement pending in the Shumacher Action.&lt;/div&gt;

&lt;div&gt;&lt;br/&gt;
  &lt;/div&gt;

&lt;div style="display:none;"&gt;&lt;br/&gt;&lt;/div&gt;
&lt;div style="text-align: justify; text-indent: 36pt; color: #000000; font-family: 'Times New Roman'; font-size: 10pt;"&gt;On July 18, 2022, Ionis filed a Form 8-K disclosing the pending settlement and attaching the Notice of Pendency of Settlement of Action.
    On September 21, 2022, the Court held a hearing to consider whether the terms of the settlement should be approved, at which hearing the Cohen Action plaintiff objected to the settlement. At the conclusion of the hearing, the Court declined to approve
    the settlement and directed the parties to meet and confer on the issue of the scope of the release. On February 7, 2023, the parties entered into an Amended Stipulation and Agreement of Compromise, Settlement and Release, which folded the Cohen Action
    into the settlement, or the Revised Settlement. The settlement did not have a material impact on our condensed consolidated financial statements. On April 24, 2023, the Court issued an Order and Final Judgment approving the Revised Settlement and
    dismissing the Shumacher and Cohen Actions, and all claims contained therein, with prejudice. The Order does not contain any admission of wrongdoing by any defendant.&lt;/div&gt;
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<TYPE>XML
<SEQUENCE>60
<FILENAME>Show.js
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
// Edgar(tm) Renderer was created by staff of the U.S. Securities and Exchange Commission.  Data and content created by government employees within the scope of their employment are not subject to domestic copyright protection. 17 U.S.C. 105.
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<DOCUMENT>
<TYPE>XML
<SEQUENCE>61
<FILENAME>report.css
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
/* Updated 2009-11-04 */
/* v2.2.0.24 */

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..report table.authRefData a {
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..report table.authRefData .hide {
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..report table.authRefData .hide a:hover {
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..report table.authRefData .body {
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..report table.authRefData table{
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/* Report Styles */
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}

/* table */
..report {
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..report hr {
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..report th.void	{
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..report .pl {
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end
</TEXT>
</DOCUMENT>
</SEC-DOCUMENT>
